bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptations to fluctuating selection in
Drosophila
Authors: Mustonen Ville , Lässig Michael
Published: February 2007

Time-dependent selection causes the adaptive evolution of new phenotypes, and this dynamics can be traced in genomic data. We have analyzed polymorphisms and substitutions in
Drosophila
, using a more sensitive inference method for adaptations than the standard population-genetic tests. We find evidence that selection itself is strongly time-dependent, with changes occurring at nearly the rate of neutral evolution. At the same time, higher than previously estimated levels of selection make adaptive responses by a factor 10–100 faster than the pace of selection changes, ensuring that adaptations are an efficient mode of evolution under time-dependent selection. The rate of selection changes is faster in noncoding DNA, i.e., the inference of functional elements can less be based on sequence conservation than for proteins. Our results suggest that selection acts not only as a constraint but as a major driving force of genomic change.
Queen pheromone modulates brain dopamine function in worker honey bees
Authors: Beggs Kyle T. , Glendining Kelly A. , Marechal Nicola M. , Vergoz Vanina , Nakamura Ikumi , Slessor Keith N. , Mercer Alison R.
Published: February 2007

Honey bee queens produce a sophisticated array of chemical signals (pheromones) that influence both the behavior and physiology of their nest mates. Most striking are the effects of queen mandibular pheromone (QMP), a chemical blend that induces young workers to feed and groom the queen and primes bees to perform colony-related tasks. But how does this pheromone operate at the cellular level? This study reveals that QMP has profound effects on dopamine pathways in the brain, pathways that play a central role in behavioral regulation and motor control. In young worker bees, dopamine levels, levels of dopamine receptor gene expression, and cellular responses to this amine are all affected by QMP. We identify homovanillyl alcohol as a key contributor to these effects and provide evidence linking QMP-induced changes in the brain to changes at a behavioral level. This study offers exciting insights into the mechanisms through which QMP operates and a deeper understanding of the queen's ability to regulate the behavior of her offspring.
Dynamic oligomeric conversions of the cytoplasmic RCK domains mediate MthK potassium channel activity
Authors: Kuo Mario Meng-Chiang , Baker Kent A. , Wong Lee , Choe Senyon
Published: February 2007

The crystal structure of the RCK-containing MthK provides a molecular framework for understanding the ligand gating mechanisms of K
+
channels. Here we examined the macroscopic currents of MthK in enlarged
Escherichia coli
membrane by patch clamp and rapid perfusion techniques and showed that the channel undergoes desensitization in seconds after activation by Ca
2+
or Cd
2+
. Additionally, MthK is inactivated by slightly acidic pH only from the cytoplasmic side. Examinations of isolated RCK domain by size-exclusion chromatography, static light scattering, analytical sedimentation, and stopped-flow spectroscopy show that Ca
2+
rapidly converts isolated RCK monomers to multimers at alkaline pH. In contrast, the RCK domain at acidic pH remains firmly dimeric regardless of Ca
2+
but restores predominantly to multimer or monomer at basic pH with or without Ca
2+
, respectively. These functional and biochemical analyses correlate the four functional states of the MthK channel with distinct oligomeric states of its RCK domains and indicate that the RCK domains undergo oligomeric conversions in modulating MthK activities.
The PsbQ protein defines cyanobacterial Photosystem II complexes with highest activity and stability
Authors: Roose Johnna L. , Kashino Yasuhiro , Pakrasi Himadri B.
Published: February 2007

Light-induced conversion of water to molecular oxygen by Photosystem II (PSII) is one of the most important enzymatic reactions in the biosphere. PSII is a multisubunit membrane protein complex with numerous associated cofactors, but it continually undergoes assembly and disassembly due to frequent light-mediated damage as a result of its normal function. Thus, at any instant, there is heterogeneity in the subunit compositions of PSII complexes within the cell. In particular, cyanobacterial PSII complexes have five associated extrinsic proteins, PsbO, PsbP, PsbQ, PsbU, and PsbV. However, little is known about the interactions of the more recently identified PsbQ protein with other components in cyanobacterial PSII. Here we show that PSII complexes can be isolated from the cyanobacterium
Synechocystis
sp. PCC 6803 on the basis of the presence of a polyhistidine-tagged PsbQ protein. Purification of PSII complexes using a tagged extrinsic protein has not been previously described, and this work conclusively demonstrates that PsbQ is present in combination with the PsbO, PsbU, and PsbV proteins in cyanobacterial PSII. Moreover, PsbQ-associated PSII complexes have higher activity and stability relative to those isolated using histidine-tagged CP47, an integral membrane protein. Therefore, we conclude that the presence of PsbQ defines the fully assembled and optimally active form of the enzyme.
Amelioration of progressive renal injury by genetic manipulation of
Klotho
gene
Authors: Haruna Yoshisuke , Kashihara Naoki , Satoh Minoru , Tomita Naruya , Namikoshi Tamehachi , Sasaki Tamaki , Fujimori Toshihiko , Xie Ping , Kanwar Yashpal S.
Published: February 2007

Klotho
, an antiaging gene with restricted organ distribution, is mainly expressed in the kidney tubules; the mutant mice have shortened life span, arteriosclerosis, anemia, and osteoporesis, features common to patients with chronic renal failure. Conceivably, the reduction of the
Klotho
gene expression may contribute to the development of kidney failure; alternatively, its overexpression may lead to the amelioration of renal injury in an ICR-derived glomerulonephritis (ICGN) mouse model with subtle immune complex-mediated disease. To address this issue, four different strains of mice were generated by cross-breeding: ICGN mice without the
Klotho
transgene (ICGN), ICGN mice with the
Klotho
transgene (ICGN/klTG), wild-type mice with the
Klotho
transgene (klTG), and wild-type mice without the
Klotho
transgene (control). At 40 weeks old, the survival rate was ≈30% in ICGN mice, and ≈70% in the ICGN/klTG group. This improvement was associated with dramatic improvement in renal functions, morphological lesions, and cytochrome
c
oxidase activity but a reduction in β-galactosidase activity (a senescence-associated protein), mitochondrial DNA fragmentation, superoxide anion generation, lipid peroxidation, and Bax protein expression and apoptosis. Interestingly, improvement was seen in both the tubular and glomerular compartments of the kidney, although
Klotho
is exclusively confined to the tubules, suggesting that its gene product has a remarkable renoprotective effect by potentially serving as a circulating hormone while mitigating the mitochondrial oxidative stress.
Assessment of nitric oxide signals by triiodide chemiluminescence
Authors: Hausladen Alfred , Rafikov Ruslan , Angelo Michael , Singel David J. , Nudler Evgeny , Stamler Jonathan S.
Published: February 2007

Nitric oxide (NO) bioactivity is mainly conveyed through reactions with iron and thiols, furnishing iron nitrosyls and
S
-nitrosothiols with wide-ranging stabilities and reactivities. Triiodide chemiluminescence methodology has been popularized as uniquely capable of quantifying these species together with NO byproducts, such as nitrite and nitrosamines. Studies with triiodide, however, have challenged basic ideas of NO biochemistry. The assay, which involves addition of multiple reagents whose chemistry is not fully understood, thus requires extensive validation: Few protein standards have in fact been characterized; NO mass balance in biological mixtures has not been verified; and recovery of species that span the range of NO-group reactivities has not been assessed. Here we report on the performance of the triiodide assay vs. photolysis chemiluminescence in side-by-side assays of multiple nitrosylated standards of varied reactivities and in assays of endogenous Fe- and
S
-nitrosylated hemoglobin. Although the photolysis method consistently gives quantitative recoveries, the yields by triiodide are variable and generally low (approaching zero with some standards and endogenous samples). Moreover, in triiodide, added chemical reagents, changes in sample pH, and altered ionic composition result in decreased recoveries and misidentification of NO species. We further show that triiodide, rather than directly and exclusively producing NO, also produces the highly potent nitrosating agent, nitrosyliodide. Overall, we find that the triiodide assay is strongly influenced by sample composition and reactivity and does not reliably identify, quantify, or differentiate NO species in complex biological mixtures.
Therapeutic anticancer efficacy of a synthetic diazonamide analog in the absence of overt toxicity
Authors: Williams Noelle S. , Burgett Anthony W. G. , Atkins Ashley S. , Wang Xiaodong , Harran Patrick G. , McKnight Steven L.
Published: February 2007

Blocking cell division through the inhibition of mitosis is one of the most successful clinical strategies for the treatment of cancer. Taxanes and vinca alkaloids are in widespread use and have demonstrated substantive therapeutic efficacy. Both classes of compounds bind directly to tubulin, a structural component of the mitotic spindle. The ubiquitous utilization of tubulin in cell division in both cancerous and normal cells, however, tempers the broad spectrum of activity of currently used antimitotics by significant toxicities in normal dividing tissue. Moreover, peripheral nerve cells that rely on microtubules to shuttle cargo along axonal processes are also damaged by tubulin-binding drugs. Thus, neutropenia and peripheral neuropathy are the most frequently cited dose-limiting toxicities of this class of chemotherapeutics. Here we report the preclinical assessment of AB-5, a structural and functional analog of the natural product diazonamide A. AB-5, like taxanes and vinca alkaloids, blocks cell division during mitosis. However, AB-5 works not by binding tubulin but rather through inhibition of a newly discovered role for ornithine-δ-aminotransferase in mitosis. We hereby report that, unlike other antimitotics, AB-5 is extremely well tolerated by mice when administered under conditions where the drug cures xenografted tumors as effectively as taxanes and vinca alkaloids. AB-5-treated mice show no weight loss, no change in overall physical appearance, and no evidence of neutropenia. These observations raise the possibility that AB-5 may have clinical utility for cancer therapy under conditions largely devoid of chemotherapeutic toxicity and suggest that further preclinical evaluation of AB-5 is warranted.
Death Receptor-induced Apoptosis Reveals a Novel Interplay between the Chromosomal Passenger Complex and CENP-C during Interphase
Authors: Faragher Alison J. , Sun Xiao-Ming , Butterworth Michael , Harper Nick , Mulheran Mike , Ruchaud Sandrine , Earnshaw William C. , Cohen Gerald M.
Published: February 2007

Despite the fact that the chromosomal passenger complex is well known to regulate kinetochore behavior in mitosis, no functional link has yet been established between the complex and kinetochore structure. In addition, remarkably little is known about how the complex targets to centromeres. Here, in a study of caspase-8 activation during death receptor-induced apoptosis in MCF-7 cells, we have found that cleaved caspase-8 rapidly translocates to the nucleus and that this translocation is correlated with loss of the centromere protein (CENP)-C, resulting in extensive disruption of centromeres. Caspase-8 activates cytoplasmic caspase-7, which is likely to be the primary caspase responsible for cleavage of CENP-C and INCENP, a key chromosomal passenger protein. Caspase-mediated cleavage of CENP-C and INCENP results in their mislocalization and the subsequent mislocalization of Aurora B kinase. Our results demonstrate that the chromosomal passenger complex is displaced from centromeres as a result of caspase activation. Furthermore, mutation of the primary caspase cleavage sites of INCENP and CENP-C and expression of noncleavable CENP-C or INCENP prevent the mislocalization of the passenger complex after caspase activation. Our studies provide the first evidence for a functional interplay between the passenger complex and CENP-C.
Conserved Actin Cysteine Residues Are Oxidative Stress Sensors That Can Regulate Cell Death in Yeast
Authors: Farah Michelle E. , Amberg David C.
Published: February 2007

Actin's functional complexity makes it a likely target of oxidative stress but also places it in a prime position to coordinate the response to oxidative stress. We have previously shown that the NADPH oxidoreductase Oye2p protects the actin cytoskeleton from oxidative stress. Here we demonstrate that the physiological consequence of actin oxidation is to accelerate cell death in yeast. Loss of Oye2p leads to reactive oxygen species accumulation, activation of the oxidative stress response, nuclear fragmentation and DNA degradation, and premature chronological aging of yeast cells. The oye2Δ phenotype can be completely suppressed by removing the potential for formation of the actin C285-C374 disulfide bond, the likely substrate of the Oye2p enzyme or by treating the cells with the clinically important reductant N-acetylcysteine. Because these two cysteines are coconserved in all actin isoforms, we theorize that we have uncovered a universal mechanism whereby actin helps to coordinate the cellular response to oxidative stress by both sensing and responding to oxidative load.
Prox1 Induces Lymphatic Endothelial Differentiation via Integrin α9 and Other Signaling Cascades
Authors: Mishima Koichi , Watabe Tetsuro , Saito Akira , Yoshimatsu Yasuhiro , Imaizumi Natsuko , Masui Shinji , Hirashima Masanori , Morisada Tohru , Oike Yuichi , Araie Makoto , Niwa Hitoshi , Kubo Hajime , Suda Toshio , Miyazono Kohei
Published: February 2007

During embryonic lymphatic development, a homeobox transcription factor Prox1 plays important roles in sprouting and migration of a subpopulation of blood vessel endothelial cells (BECs) toward VEGF-C–expressing cells. However, effects of Prox1 on endothelial cellular behavior remain to be elucidated. Here, we show that Prox1, via induction of integrin α9 expression, inhibits sheet formation and stimulates motility of endothelial cells. Prox1-expressing BECs preferentially migrated toward VEGF-C via up-regulation of the expression of integrin α9 and VEGF receptor 3 (VEGFR3). In mouse embryos, expression of VEGFR3 and integrin α9 is increased in Prox1-expressing lymphatic endothelial cells (LECs) compared with BECs. Knockdown of Prox1 expression in human LECs led to decrease in the expression of integrin α9 and VEGFR3, resulting in the decreased chemotaxes toward VEGF-C. These findings suggest that Prox1 plays important roles in conferring and maintaining the characteristics of LECs by modulating multiple signaling cascades and that integrin α9 may function as a key regulator of lymphangiogenesis acting downstream of Prox1.
Evolution of a Tumorigenic Property Conferred by Glycophosphatidyl-Inositol Membrane Anchors of Carcinoembryonic Antigen Gene Family Members during the Primate Radiation
Authors: Naghibalhossaini Fakhraddin , Yoder Anne D. , Tobi Martin , Stanners Clifford P.
Published: February 2007

GPI membrane anchors of cell surface glycoproteins have been shown to confer functional properties that are different from their transmembrane (TM)-anchored counterparts. For the human carcinoembryonic antigen (CEA) family, a subfamily of the immunoglobulin superfamily, conversion of the mode of membrane linkage from TM to GPI confers radical changes in function: from tumor suppression or neutrality toward inhibition of differentiation and anoikis and distortion of tissue architecture, thereby contributing to tumorigenesis. We show here that GPI anchorage in the CEA family evolved twice independently in primates, very likely from more primitive TM anchors, by different packages of mutations. Both mutational packages, one package found in many primates, including humans, and a second, novel package found only in the Cebidae radiation of New World monkeys, give rise to efficiently processed GPI-linked proteins. Both types of GPI anchors mediate inhibition of cell differentiation. The estimated rate of nonsynonymous mutations (Ka) in the anchor-determining domain for conversion from TM to GPI anchorage in the CEA family that were fixed during evolution in these primates is 7 times higher than the average Kain primates, indicating positive selection. These results suggest therefore that the functional changes mediated by CEA GPI anchors, including the inhibition of differentiation and anoikis, could be adaptive and advantageous.
Juice Powder Concentrate and Systemic Blood Pressure, Progression of Coronary Artery Calcium and Antioxidant Status in Hypertensive Subjects: A Pilot Study
Authors: Houston M. C. , Cooil B. , Olafsson B. J. , Raggi P.
Published: February 2007

Because micronutrients from plants may have beneficial cardiovascular effects, the hypothesis that an encapsulated juice powder concentrate might affect several measures of vascular health was tested in free living adults at low cardiovascular risk. Blood pressure, vascular compliance, lipid and antioxidant markers, and serial electron beam tomography (to calculate a coronary artery calcium score as a measure of atherosclerosis burden), were monitored in 51 pre‐hypertensive and hypertensive subjects over 2 years. By the end of follow‐up, systolic and diastolic blood pressure decreased significantly (−2.4 ± 1.0 mmHg, P < 0.05 and −2.2 ± 0.6 mmHg, P < 0.001), and large artery compliance improved significantly (1.9 ± 0.6 ml mmHg−1 × 100, P < 0.01). The progression of coronary artery calcium score was smaller than expected compared with a historical database (P < 0.001). Laboratory testing showed a significant decrease in homocysteine (P = 0.05), HDL cholesterol (P = 0.025) and Apo A (P = 0.004), as well as a significant increase in β‐carotene, folate, Co‐Q10 and α‐tocopherol (all P < 0.001). The phytonutrient concentrate we utilized induced several favorable modifications of markers of vascular health in the subjects. This study supports the notion that plant nutrients are important components of a heart healthy diet.
Designing biological systems
Authors: Drubin David A. , Way Jeffrey C. , Silver Pamela A.
Published: February 2007

The design of artificial biological systems and the understanding of their natural counterparts are key objectives of the emerging discipline of synthetic biology. Toward both ends, research in synthetic biology has primarily focused on the construction of simple devices, such as transcription-based oscillators and switches. Construction of such devices should provide us with insight on the design of natural systems, indicating whether our understanding is complete or whether there are still gaps in our knowledge. Construction of simple biological systems may also lay the groundwork for the construction of more complex systems that have practical utility. To realize its full potential, biological systems design borrows from the allied fields of protein design and metabolic engineering. In this review, we describe the scientific accomplishments in this field, as well as its forays into biological part standardization and education of future biological designers.
DefectiveN-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development
Authors: Abramsson Alexandra , Kurup Sindhulakshmi , Busse Marta , Yamada Shuhei , Lindblom Per , Schallmeiner Edith , Stenzel Denise , Sauvaget Dominique , Ledin Johan , Ringvall Maria , Landegren Ulf , Kjellén Lena , Bondjers Göran , Li Jin-ping , Lindahl Ulf , Spillmann Dorothe , Betsholtz Christer , Gerhardt Holger
Published: February 2007

During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction ofN-sulfation due to deficiency inN-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. ReducedN-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensivelyN-and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spacedN-sulfated domains to retain PDGF-BB and activate PDGF receptor β (PDGFRβ) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.
Cdk phosphorylation of the Ste11 transcription factor constrains differentiation-specific transcription to G1
Authors: Kjærulff Søren , Andersen Nicoline Resen , Borup Mia Trolle , Nielsen Olaf
Published: February 2007

Eukaryotic cells normally differentiate from G1; here we investigate the mechanism preventing expression of differentiation-specific genes outside G1. In fission yeast, induction of the transcription factor Ste11 triggers sexual differentiation. We find that Ste11 is only active in G1when Cdk activity is low. In the remaining part of the cell cycle, Ste11 becomes Cdk-phosphorylated at Thr 82 (T82), which inhibits its DNA-binding activity. Since theste11gene is autoregulated and the Ste11 protein is highly unstable, this Cdk switch rapidly extinguishes Ste11 activity when cells enter S phase. When we mutated T82 to aspartic acid, mimicking constant phosphorylation, cells no longer underwent differentiation. Conversely, changing T82 to alanine rendered Ste11-controlled transcription constitutive through the cell cycle, and allowed mating from S phase with increased frequency. Thus, Cdk phosphorylation mediates periodic expression of Ste11 and its target genes, and we suggest this to be part of the mechanism restricting differentiation to G1.
Osteomyelitis due to arsenic trioxide use for tooth devitalization
Authors: Dumlu A. , Yalcinkaya S. , Olgac V. , Güvercin M.
Published: February 2007

Aim:  To present a case of osteomyelitis that was caused by the use of arsenic trioxide during root canal treatment in a mandibular left first molar.

Summary:  Arsenic was once in common use to devitalize inflammed pulp tissue before root canal treatment. Its prolonged application or leakage leads to toxic effects beyond the pulp tissue, and necrosis of periodontal tissues and supporting alveolar bone has been described. This report presents a case of osteomyelitis resulting from leakage of arsenic trioxide used in pulp devitalization. Sequestrectomy and excision of non‐vital alveolar bone was performed to treat the severe tissue necrosis.

Key learning points

• Agents containing arsenic are still employed by some clinicians and may be encountered when patients present with tissue destruction resulting from their use.

• Dental practitioners should be aware that arsenic paste may diffuse into periodontal tissues through apical, lateral or accessory canals, through perforations and around leaking restorations.

• Osteomyelitis caused by arsenic trioxide can be treated by a combination of pharmacotherapeutic and invasive surgical methods.

• Arsenic pastes have no place in endodontic practice.
Congenital melanocytic nevi and nevus spilus have a tendency to follow the lines of Blaschko: An examination of 200 cases
Authors: HANAYAMA Hiromi , TERASHI Hiroto , HASHIKAWA Kazunobu , TAHARA Shinya
Published: February 2007

There have been few reports about the characteristics of the pigmentary arrangement of congenital melanocytic nevi (CMN) and nevus spilus (NS). Though the lines of Blaschko, which don't correspond to other lines such as Langer's lines and skin dermatomes, are well known to be followed by some rare pigmentary disorders, the relationship between these two disorders and the lines of Blaschko has not been discussed. Therefore, through an examination of 200 cases, we investigated whether or not the arrangement of CMN and NS follow the lines of Blaschko. Thirty‐nine out of 92 cases (42.4%) of CMN and 67 out of 108 cases (62.0%) of NS were considered to follow the lines of Blaschko. Today, the idea is widely accepted that two functionally different cells proliferate during early embryogenesis of the skin which is caused from mosaicism and, as a result, the lines of Blaschko appear visually. In our results, we found that there were some cases of CMN and NS which showed a relationship with the lines of Blaschko, which is meaningful considering that the lesions and the lines are both related to pigmentary gene anomalies. The result was compared with CMN and NS by the χ2 test. NS showed a predominant tendency to follow the lines with a significant difference (P = 0.0055). This may indicate that the lines of Blaschko reflect more clearly the proliferation of the epidermal cells than other cells in growth of the skin of the embryo. Further studies are required to elucidate the reason why some cases follow these lines and others do not.
Development of atopic dermatitis‐specific communication tools: Interview form and question and answer brochure
Authors: OGAWA Sachiko , UCHI Hiroshi , FUKAGAWA Shuji , TAKEUCHI Satoshi , NAKAHARA Takeshi , KATO Mariko , KOKUBA Hisashi , FURUE Masutaka
Published: February 2007

At first consultation, it is sometimes difficult for patients to decide which questions they want to ask most. We investigated whether an improvement in interview forms would identify the questions that patients want to ask doctors and help patients express their needs. First, we developed a two‐part interview form specifically for atopic dermatitis (AD) patients. The first part was related to diagnosis. In the second part, we determined the most frequently asked questions by patients in daily AD clinics and included these in a prompt interview form, which we called “Questions You May Want to Ask”. We compared this new interview form with the standard interview one used in our hospital. Then we made a brochure with answers to those questions. Finally, we evaluated the usefulness of these communication tools. The usefulness of the AD‐specific interview form and the answer brochure was validated by patients and/or their surrogates. The majority of them recognized the necessity for and usefulness of these tools to communicate appropriately with their doctors. The answer brochure significantly increased their understanding of AD. The AD‐specific interview form and the answer brochure are useful communication tools to improve doctor–patient relationships.
Fluid‐fluid level in a giant epidermal cyst of the buttock
Authors: TAKEMURA Noriko , FUJII Norikazu , SHIBATA Chikako , KAWANO Akiko , FUJIMOTO Noriki , UENISHI Toshiaki , TANAKA Toshihiro
Published: February 2007

We describe a case of a giant epidermal cyst of the buttock that demonstrated a fluid‐fluid level on imaging. There have been no previously reported cases of epidermal cysts containing a fluid‐fluid level, so our case was considered to be very exceptional. A 39‐year‐old man had had a slowly enlarging giant subcutaneous mass in the left buttock for more than 10 years. It was elastic‐soft, well‐circumscribed and smooth‐surfaced. Ultrasonography showed a well‐circumscribed hypoechoic mass with a fluid‐fluid level in the subcutis of the left buttock. Magnetic resonance imaging (MRI) showed a well‐circumscribed cystic mass measuring 8 cm × 5.5 cm × 5.5 cm in the same place that the ultrasonography indicated. It was hypointense on the T1‐weighted image, hyperintense on the T2‐weighted image, and contained a fluid‐fluid level on both the T1‐ and T2‐weighted images. It bordered on the anus, but neither adhered nor formed a fistula with it. A surgical excision was performed. The mass was diagnosed histopathologically as an epidermal cyst. The occurrence of fluid‐fluid levels in epidermal cysts should be kept in mind in the differential diagnosis of subcutaneous soft tissue tumors.
Late‐onset self‐healing reticulohistiocytosis: Pediatric case of Hashimoto–Pritzker type Langerhans cell histiocytosis
Authors: NAKAHIGASHI Kyoko , OHTA Miyuki , SAKAI Rie , SUGIMOTO Yasushi , IKOMA Yukiko , HORIGUCHI Yuji
Published: February 2007

An 8‐year‐old otherwise healthy girl presented with a 3‐month history of multiple asymptomatic, reddish‐brown papules over the face and upper limbs. Histopathological and immunohistochemical examinations demonstrated an infiltrate of mononuclear cells containing abundant histiocytic cells in the dermis, and microabscess‐like accumulation of the histiocytic cells in the epidermis. The histiocytic cells were positive for antibodies against S‐100 protein and CD1a, but negative for anti‐CD68. Lag and anti‐langerin monoclonal antibodies reacted more weakly with these histiocytic cells than with Langerhans cells in the surrounding epidermis. The skin lesions spontaneously regressed within the following 3 months, and neither systemic involvement nor local recurrence was observed during the next 10 months. This case should be categorized as congenital self‐healing reticulohistiocytosis (Hashimoto–Pritzker), although the onset was not early in life.
Cutis marmorata telangiectatica congenita and chronic autoimmune urticaria in a young man
Authors: MELANI Lucilla , ANTIGA Emiliano , TORCHIA Daniele , GIOMI Barbara , MASSI Daniela , CAPRONI Marzia , EMMI Lorenzo , FABBRI Paolo
Published: February 2007

A 20‐year‐old man with mental impairment, was referred to us for evaluation of recurring idiopathic urticaria episodes, characterized by a diffuse spreading of wheals and severe itching lacking response to traditional antihistamines. Upon physical examination, he showed a persistent, generalized, reticular, red‐bluish vascular skin pattern in association with diffuse arborizing telangiectasias. Such lesions were present from an early age. Laboratory and instrumental tests, performed in order to exclude any condition associated with livedo did not evidence pathological results. He was found to be positive for antinuclear autoantibodies (ANA; 1:640). Histopathologically, numerous dilated capillary vessels associated with sparse extravasated erythrocytes were observed in the upper dermis. We performed an autologous serum skin test (ASST), which resulted in a positive, suggesting an autoimmune basis of the condition. On the basis of clinical and histopathological findings, and in the absence of other clinical and laboratory data suggesting other neoplastic, immunological or systemic diseases, the diagnosis of cutis marmorata telangiectatica congenita (CMTC) associated with chronic autoimmune urticaria (CAIU) was made. CMTC is a rare congenital vascular disorder, consisting in an anomalous, persistent, red‐bluish marbling of the skin, that can be associated with a wide spectrum of cutaneous and extracutaneous anomalies. In our case, neither physical examination nor instrumental investigation demonstrated any of these anomalies, with the exception of cognitive impairment. We report this case because of the rarity of a diagnosis of CMTC in an adult patient, because this condition has almost always previously been diagnosed in infancy, or it comes to observation because of the presence of associated disorders, as in our case for chronic urticaria.
The monoamine oxidase A (MAO‐A) gene, family function and maltreatment as predictors of destructive behaviour during male adolescent alcohol consumption
Authors: Nilsson Kent W. , Sjöberg Rickard L. , Wargelius Hanna‐Linn , Leppert Jerzy , Lindström Leif , Oreland Lars
Published: February 2007

Aim  To investigate possible interactions between a polymorphism in the monoamine oxidase A (MAO‐A) gene promoter, family relations and maltreatment/sexual abuse on adolescent alcohol‐related problem behaviour among male adolescents.

Design, setting and participants  A cross‐sectional study of a randomized sample of 66 male individuals from a total population of 16‐ and 19‐year adolescents from a Swedish county. Boys, who volunteered to participate answering an alcohol‐related problem/behaviour questionnaire, were investigated with regard to interactions between such problems, family function, maltreatment and MAO‐A genotype.

Measurements  MAO‐A genotype, family relations history, history of being maltreated or abused and alcohol‐related problem behaviour.

Findings  Boys with the short (three‐repeat) variant of the MAO‐A gene, who had been maltreated/abused or came from families with poor relations, showed significantly higher scores of alcohol‐related problems. We also found that maltreatment/abuse independently showed the strongest relation to alcohol‐related problems among boys in our model.

Conclusions  The results suggest that both maltreatment and MAO‐A genotype may be useful for the understanding of male adolescent alcohol‐related problem behaviour.
The impact of post‐traumatic stress disorder on treatment outcomes for heroin dependence
Authors: Mills Katherine L. , Teesson Maree , Ross Joanne , Darke Shane
Published: February 2007

Aims To examine the impact of post‐traumatic stress disorder (PTSD) on 2‐year treatment outcomes for heroin dependence.

Design Prospective longitudinal study.

Participants Data were obtained from a predominantly treatment seeking sample of 615 dependent heroin users who were followed‐up at 3, 12 and 24 months (follow‐up rates: 89%, 81% and 76%, respectively).

Measurements Outcomes examined include treatment retention and exposure, substance use, general physical and mental health and employment.

Findings Despite improvements in substance use, PTSD was associated with continued physical (β− 1.69, SE 0.61,P < 0.01) and mental disability (β− 2.07, SE 0.66,P < 0.01), and reduced occupational functioning (OR 0.67, 95% CI: 0.48–0.93) throughout the 2‐year follow‐up.

Conclusions Although conventional treatment services are successful in producing improvements in substance use and associated disability, the disability associated with PTSD remains. An intervention targeting both heroin dependence and PTSD may help to improve the outcomes of those with PTSD.
Methadone maintenance treatment: the balance between life‐saving treatment and fatal poisonings
Authors: Fugelstad A. , Stenbacka M. , Leifman A. , Nylander M. , Thiblin I.
Published: February 2007

Aim  To determine the total mortality related to the Stockholm methadone programme during the period 1988–2000, both the mortality related to the treatment and fatal methadone intoxications in the Stockholm area during the same period.

Methods  The study comprised all individuals (n = 848) who had been in contact with the methadone programme in Stockholm during the study period, including those patients who had been discharged from treatment and those opiate users who had applied for but not received methadone treatment. All deaths that had been the subject of medico‐legal examination at the Department of Forensic Medicine in Stockholm where methadone was found in blood or urine were also analysed during the same period.

Results  The mortality was lower among those opiate users who remained in maintenance treatment and 91% of the deceased individuals had died due to natural causes, in most cases related to HIV or hepatitis C, acquired before admission to the programme. Those who had been discharged from methadone treatment had a 20 times higher risk of dying from unnatural causes compared to the patients who remained in treatment. The majority died due to heroin injections (‘overdoses’). Eighty‐nine cases of fatal methadone intoxication were found, but in only two of these cases was there evidence of leakage from maintenance treatment.

Conclusion  The ‘high threshold programme’ is safe as long as the patients remain in treatment and there are very few deaths due to leakage from the programme. However, there is a high mortality among those discharged from the programme and only a minority of the heroin users in Stockholm had applied for treatment.
Alcohol tax cuts and increase in alcohol‐positive sudden deaths—a time‐series intervention analysis
Authors: Koski Anna , Sirén Reino , Vuori Erkki , Poikolainen Kari
Published: February 2007

Aims  The impact of alcohol regulation changes in Finland during 2004 on alcohol‐positive sudden deaths was analysed, focusing on: (1) removal of traveller's allowance quotas on alcohol imports from other European Union (EU) countries, (2) lowering of Finnish alcohol excise duty rates and (3) Estonia joining the EU.

Design  The impact of these changes was estimated using an autoregressive integrated moving average (ARIMA) analytical technique. Post‐mortem forensic toxicology data were analysed over a 15‐year period to account for seasonal and long‐term variation. In all, the data comprised a weekly series of 33 782 alcohol‐positive cases (at least 0.20 mg/g alcohol in blood) and a control series of 37 617 alcohol‐negative cases.

Setting  Finland in 1990–2004.

Findings  The liberation of traveller's allowances had no material impact on alcohol‐positive sudden deaths, but the impact of alcohol tax cuts in March 2004 was significant, resulting in an estimated eight additional alcohol‐positive deaths per week, which is a 17% increase compared with the weekly average of 2003. The impact associated with Estonia joining the EU was not statistically significant. In the models applied to the control series of alcohol‐negative deaths, none of the impact coefficients was statistically significant.

Conclusions  Alcohol tax cuts were associated with an increase in the number of sudden deaths involving alcohol. This parallels the reported increases in alcohol consumption and alcohol‐related causes of death in 2004 in Finland.
Attentional re‐training decreases attentional bias in heavy drinkers without generalization
Authors: Schoenmakers Tim , Wiers Reinout W. , Jones Barry T. , Bruce Gillian , Jansen Anita T. M.
Published: February 2007

Aims  To examine whether alcohol‐related attentional bias (AB) can be reduced by training heavy drinkers to attend to soft drinks as an alternative to alcohol. Diminishing AB is important because AB has been suggested to be a significant factor in the development, maintenance and relapse of addictive behaviours. AB was trained in a clinically relevant design, and we studied the generalization of this training.

Design, participants and intervention  We assigned randomly 106 heavy drinking male college and university students to the attentional re‐training (AR; modified visual‐probe task) or control condition (standard visual‐probe task).

Setting  Laboratory at Maastricht University.

Measurements  We measured the effects of AR on the visual‐probe task with stimuli that were presented in the AR and with new stimuli, and on an alternative measure of AB, the flicker paradigm. We further measured effects on craving and preference for either an alcohol beverage or a soft drink.

Findings  After AR, participants had learned to avoid alcohol stimuli and had developed an AB for soft drinks. This effect was restricted to stimuli used in the AR. The flicker task, where AB for alcohol was found in both the AR and control groups, was not affected by the AR. No effect was found on craving and the preference task.

Conclusions  Although heavy drinkers can learn to attend selectively to an alternative category for alcohol, a single AR is not sufficient to decrease symptoms of problem drinking.
Childhood social disadvantage and smoking in adulthood: results of a 25‐year longitudinal study
Authors: Fergusson David M. , Horwood L. John , Boden Joseph M. , Jenkin Gabrielle
Published: February 2007

Aim  To examine the associations between exposure to socio‐economic disadvantage in childhood and smoking in adulthood.

Design  A 25‐year longitudinal study of the health, development and adjustment of a birth cohort of 1265 New Zealand children.

Measurements  Assessments of childhood socio‐economic disadvantage, smoking in adulthood and potential mediating pathways, including: parental education, family socio‐economic status, family living standards and family income; smoking frequency and nicotine dependence at age 25 years; child IQ, educational achievement by age 18 years, conduct problems ages 14–16 years, parental smoking 0–16 years and peer smoking at 16 years.

Findings  Smoking at age 25 was correlated significantly (P < 0.0001) with increasing childhood socio‐economic disadvantage. Further, indicators of childhood socio‐economic disadvantage were correlated significantly (P < 0.0001) with the intervening variables of childhood intelligence, school achievement, conduct problems and exposure to parental and peer smoking; which in turn were correlated significantly (P < 0.0001) with measures of smoking at age 25. Structural equation modelling suggested that the linkages between the latent factor of childhood disadvantage and later smoking were explained largely by a series of pathways involving cognitive/educational factors, adolescent behavioural adjustment and exposure to parental and peer smoking.

Conclusions  The current study suggested that smoking in adulthood is influenced by childhood socio‐economic disadvantage via the mediating pathways of cognitive/educational factors, adolescent behaviour and parental and peer smoking.
Effects of rapid smoking on post‐cessation urges to smoke
Authors: McRobbie Hayden , Hajek Peter
Published: February 2007

Context  Rapid smoking (RS) is a smoking cessation technique with sufficient indications of promise to warrant further investigation. The main presumed effect of RS is on reducing desire to smoke.

Aim  To evaluate the effect of a single session of RS immediately prior to quitting smoking on urges to smoke over the first week of abstinence.

Design  Randomized controlled trial.

Setting  Specialist smoking cessation clinic (SSCC).

Participants  A total of 100 smokers attending the quit day session.

Intervention  Participants in the rapid smoking group underwent a single session of RS immediately prior to quitting smoking. Participants in the control group watched a health promotion video on giving up smoking.

Primary outcome measures  Ratings of urges to smoke in the first 24 hours and 1 week of abstinence.

Findings  The RS procedure was well tolerated. It led to significantly lower urges to smoke compared to the control procedure during the first 24 hours (mean rating of 2.6 versus 3.2, P < 0.001) and the first week of abstinence (1.8 versus 2.5, P < 0.01). In patients abstinent for 4 weeks, urges to smoke were low and the difference was no longer significant (1.4 versus 1.8).

Conclusion  RS has an ‘active ingredient’ (craving reduction) and its effects on smoking cessation may merit further examination using modern rigorous methodology.
Ifosphamide, etoposide and epirubicin is an effective combined salvage and peripheral blood stem cell mobilisation regimen for transplant‐eligible patients with non‐Hodgkin lymphoma and Hodgkin disease
Authors: Bishton Mark J. , Lush Richard J. , Byrne Jenny L. , Russell Nigel H. , Shaw Bronwen E. , Haynes Andrew P.
Published: February 2007

A total of 143 patients with relapsed (n =  90), primary refractory (n = 32) and first line chemotherapy responsive (n = 21) non‐Hodgkin lymphoma (NHL) and Hodgkin disease (HD) were treated with IVE (ifosphamide, etoposide and epirubicin) chemotherapy with the intent to proceed to high‐dose therapy with either autologous or allogeneic transplantation, following peripheral blood stem cell mobilisation. A major response (complete/partial response) to IVE was seen in 115 patients (80·4%) with 5‐year overall survival (OS) and event free survival (EFS) of 53% and 43%, respectively. Subgroup analysis showed overall response rates of 93·1% for HD with a 5‐year OS and EFS of 62% and 52% respectively, while NHL showed response rates of 78·0% with 5‐year OS and EFS of 50% and 39% respectively. The median number of CD34 +ve cells mobilised following IVE was 7·86 × 106 (range 1·72–42·91 × 106), with 60% mobilising >2 × 106/kg in a single collection. Grade IV neutropenia was seen in 79·6% patients and 77/270 cycles required intravenous antibiotic treatment. We conclude that IVE has a high response rate across a range of refractory and relapsed lymphoma with acceptable toxicity and excellent PBSC mobilising characteristics.
Metastases to the thyroid gland: prevalence, clinicopathological aspects and prognosis: a 10‐year experience
Authors: Papi Giampaolo , Fadda Guido , Corsello Salvatore Maria , Corrado Stefania , Rossi Esther Diana , Radighieri Elena , Miraglia Antonella , Carani Cesare , Pontecorvi Alfredo
Published: February 2007

Background  Metastases to thyroid (TM) are rarely observed in the clinical practice.

Objective  To assess the prevalence, clinicopathological aspects and prognosis of TM, and to evaluate the role of thyroidectomy in the management of TM.

Methods  The pathology files (databases) of two Italian Pathology Units were searched for thyroid cytology (FNAC) and histology reports covering the time period January 1993 through December 2003.

Results  Thirty‐six cases of TM were found, accounting for 0·13% of thyroidectomies and 0·07% of FNAC. The main site of origin of TM was the lung, followed by oesophagus, breast and kidney. TM patients were divided into two groups, based on whether they were (Group 1) or were not (Group 2) submitted to surgery. Thirty‐five subjects diagnosed with the same primary tumours as TM patients, but without TM, served as controls. The mean patient age, the mean time from diagnosis of primary tumour to TM detection, and the mean survival time did not significantly differ in Group 1 and Group 2 (63·2 ± 1·6 vs. 66·6 ± 2·9 years, 24·7 ± 8·6 vs. 19·7 ± 4·4 months and 24·3 ± 4·9 vs. 39 ± 9·9 months, respectively). In contrast, the mean time from detection of TM to death was longer in Group 1 than in Group 2 (14·3 ± 2·5 vs. 4·5 ± 0·5 months, respectively; P = 0·002). The overall survival of TM patients and control subjects was not significantly different (33·7 ± 6·6 vs. 32·3 ± 6 months).

Conclusions  TM is a rare event, is more frequent in patients older than 60 years, and has the same impact on prognosis as nonthyroidal metastases. Although thyroidectomy may be useful to avoid further dissemination of the primary tumour in case of solitary TM, it does not contribute to prolonging patient's life.