bluuebunny/crossref_metadata_2025 huggingface dataset:
The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo
Authors: Weston Victoria J. , Oldreive Ceri E. , Skowronska Anna , Oscier David G. , Pratt Guy , Dyer Martin J. S. , Smith Graeme , Powell Judy E. , Rudzki Zbigniew , Kearns Pamela , Moss Paul A. H. , Taylor A. Malcolm R. , Stankovic Tatjana
Published: August 2010

The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.
The type IV pilin, PilA, is required for full virulence of Francisella tularensis subspecies tularensis
Authors: Forslund Anna-Lena , Salomonsson Emelie Näslund , Golovliov Igor , Kuoppa Kerstin , Michell Stephen , Titball Richard , Oyston Petra , Noppa Laila , Sjöstedt Anders , Forsberg Åke
Published: August 2010

Background

All four Francisella tularensis subspecies possess gene clusters with potential to express type IV pili (Tfp). These clusters include putative pilin genes, as well as pilB, pilC and pilQ, required for secretion and assembly of Tfp. A hallmark of Tfp is the ability to retract the pilus upon surface contact, a property mediated by the ATPase PilT. Interestingly, out of the two major human pathogenic subspecies only the highly virulent type A strains have a functional pilT gene.

Results

In a previous study, we were able to show that one pilin gene, pilA, was essential for virulence of a type B strain in a mouse infection model. In this work we have examined the role of several Tfp genes in the virulence of the pathogenic type A strain SCHU S4. pilA, pilC, pilQ, and pilT were mutated by in-frame deletion mutagenesis. Interestingly, when mice were infected with a mixture of each mutant strain and the wild-type strain, the pilA, pilC and pilQ mutants were out-competed, while the pilT mutant was equally competitive as the wild-type.

Conclusions

This suggests that expression and surface localisation of PilA contribute to virulence in the highly virulent type A strain, while PilT was dispensable for virulence in the mouse infection model.
Transpositional reactivation of the Dart transposon family in rice lines derived from introgressive hybridization with Zizania latifolia
Authors: Wang Ningning , Wang Hongyan , Wang Hui , Zhang Di , Wu Ying , Ou Xiufang , Liu Shuang , Dong Zhenying , Liu Bao
Published: August 2010

Background

It is widely recognized that interspecific hybridization may induce "genome shock", and lead to genetic and epigenetic instabilities in the resultant hybrids and/or backcrossed introgressants. A prominent component involved in the genome shock is reactivation of cryptic transposable elements (TEs) in the hybrid genome, which is often associated with alteration in the elements' epigenetic modifications like cytosine DNA methylation. We have previously reported that introgressants derived from hybridization between Oryza sativa (rice) and Zizania latifolia manifested substantial methylation re-patterning and rampant mobilization of two TEs, a copia retrotransposon Tos17 and a MITE mPing. It was not known however whether other types of TEs had also been transpositionally reactivated in these introgressants, their relevance to alteration in cytosine methylation, and their impact on expression of adjacent cellular genes.

Results

We document in this study that the Dart TE family was transpositionally reactivated followed by stabilization in all three studied introgressants (RZ1, RZ2 and RZ35) derived from introgressive hybridization between rice (cv. Matsumae) and Z. latifolia, while the TEs remained quiescent in the recipient rice genome. Transposon-display (TD) and sequencing verified the element's mobility and mapped the excisions and re-insertions to the rice chromosomes. Methylation-sensitive Southern blotting showed that the Dart TEs were heavily methylated along their entire length, and moderate alteration in cytosine methylation patterns occurred in the introgressants relative to their rice parental line. Real-time qRT-PCR quantification on the relative transcript abundance of six single-copy genes flanking the newly excised or inserted Dart-related TE copies indicated that whereas marked difference in the expression of all four genes in both tissues (leaf and root) were detected between the introgressants and their rice parental line under both normal and various stress conditions, the difference showed little association with the presence or absence of the newly mobilized Dart-related TEs.

Conclusion

Introgressive hybridization has induced transpositional reactivation of the otherwise immobile Dart-related TEs in the parental rice line (cv. Matsumae), which was accompanied with a moderate alteration in the element's cytosine methylation. Significant difference in expression of the Dart-adjacent genes occurred between the introgressants and their rice parental line under both normal and various abiotic stress conditions, but the alteration in gene expression was not coupled with the TEs.
Molecular epidemiology of Hepatitis C virus genotypes in Khyber Pakhtoonkhaw of Pakistan
Authors: Ali Amjad , Ahmed Habib , Idrees Muhammad
Published: August 2010

Six major Hepatitis C virus (HCV) genotypes and hundreds of subtypes have been identified globally. All these genotypes are generally studied for epidemiology, their vaccine development and clinical management. This article comments the frequency distribution of various HCV genotypes circulate in different areas/districts of Khyber Pakhtoonkhaw Province of Pakistan. Sum of 415 HCV RNA PCR positive sera samples were tested by a molecular genotyping assay. Data analysis revealed that out of these 415 HCV RNA positive patients 243 were males and 172 were females. Distribution breakup of the patients was 135, 58, 51, 51, 36, 32, 6, 7and 9 patients come from the districts of Abbottabad, Mardan, Pehawar, Swat, Haripure, Swabi and Dera Ismail Khan, respectively. Out of the tested samples, genotype specific PCR fragments were observed in 299 (74.82%) patient serum samples. The distribution of genotypes of the typeable samples was as fallows: 3 patients (0.72%) each were infected with genotype 1a and genotype 1b; 240 patients (80.26%) of genotype 3a; 25 patients (6.00%) genotype 3b; and 28 patients (6.73%) were observed as with mixed genotypic infection. Sums of 116 serum samples (27.88%) were still found untypeable by the used molecular genotyping system.

In conclusion, HCV genotypes 1a, 1b, 3a and 3b are distributed in various parts of KPK among which the genotype 3a is the most frequent genotype.
Ultrasensitive Responses and Specificity in Cell Signaling
Authors: Haney Seth , Bardwell Lee , Nie Qing
Published: August 2010

Background

Interconnected cell signaling pathways are able to efficiently and accurately transmit a multitude of different signals, despite an inherent potential for undesirable levels of cross-talk. To ensure that an appropriate response is produced, biological systems have evolved network-level mechanisms that insulate pathways from crosstalk and prevent 'leaking' or 'spillover' between pathways. Many signaling pathways have been shown to respond in an ultrasensitive (switch-like) fashion to graded input, and this behavior may influence specificity. The relationship of ultrasensitivity to signaling specificity has not been extensively explored.

Results

We studied the behavior of simple mathematical models of signaling networks composed of two interconnected pathways that share an intermediate component, asking if the two pathways in the network could exhibit bothoutput specificity(preferentially activate their own output) andinput fidelity(preferentially respond to their own input). Previous results with weakly-activated pathways indicated that neither mutual specificity nor mutual fidelity were obtainable in the absence of an insulating mechanism, such as cross-pathway inhibition, combinatorial signaling or scaffolding/compartmentalization. Here we found that mutual specificity is obtainable for hyperbolic or ultrasensitive pathways, even in the absence of an insulating mechanism. However, mutual fidelity is impossible at steady-state, even if pathways are hyperbolic or ultrasensitive. Nevertheless, ultrasensitivity does provide advantages in attaining specificity and fidelity to networks that contain an insulating mechanism. For networks featuring cross-pathway inhibition or combinatorial signaling, ultrasensitive activation can increase specificity in a limited way, and can only be utilized by one of the two pathways. In contrast, for networks featuring scaffolding/compartmentalization, ultrasensitive activation of both pathways can dramatically improve network specificity.

Conclusions

There are constraints to obtaining performance objectives associated with signaling specificity; such constraints may have influenced the evolution of signal transduction networks. Notably, input fidelity (preferential response to an authentic input) is a more difficult objective to achieve than output specificity (preferential targeting to an authentic output). Indeed, mutual fidelity is impossible in the absence of an insulating mechanism, even if pathways are ultrasensitive. Ultrasensitivity does, however, significantly enhance the performance of several insulating mechanisms. In particular, the ultrasensitive activation of both pathways can provide substantial improvement to networks containing scaffolding/compartmentalization.
Basic Mechanisms of Arsenic Trioxide (ATO)-Induced Apoptosis in Human Leukemia (HL-60) Cells
Authors: Yedjou Clement , Tchounwou Paul , Jenkins John , McMurray Robert
Published: August 2010

Background

Acute promyelocytic leukemia (APL) is a blood cancer that affects people of all ages and strikes about 1,500 patients in the United States each year. The standard treatment of APL has been based on the combined administration of all-trans retinoic acid and chemotherapy including anthracyclins and cytarabine. However, 10-20% of patients relapse, with their disease becoming resistant to conventional treatment. Recently the Food and Drug Administration has approved the use of arsenic trioxide (ATO) or Trisenox for the treatment of APL, based on clinical studies showing a complete remission, especially in relapsed patients. In a recently published study we demonstrated that ATO pharmacology as an anti-cancer drug is associated with its cytotoxic and genotoxic effects in human leukemia cells.

Methods

In the present study, we further investigated the apoptotic mechanisms of ATO toxicity using the HL-60 cell line as a test model. Apoptosis was measured by flow cytometry analysis of phosphatidylserine externalization (Annexin V assay) and caspase 3 activity, and by DNA laddering assay.

Results

Flow cytometry data showed a strong dose-response relationship between ATO exposure and Annexin-V positive HL-60 cells. Similarly, a statistically significant and dose-dependent increase (p < 0.05) was recorded with regard to caspase 3 activity in HL60 cells undergoing late apoptosis. These results were confirmed by data of DNA laddering assay showing a clear evidence of nucleosomal DNA fragmentation in ATO-treated cells.

Conclusion

Taken together, our research demonstrated that ATO represents an apoptosis-inducing agent and its apoptotic mechanisms involve phosphatidylserine externalization, caspase 3 activation and nucleosomal DNA fragmentation.
Monocytes/macrophages express chemokine receptor CCR9 in rheumatoid arthritis and CCL25 stimulates their differentiation
Authors: Schmutz Caroline , Cartwright Alison , Williams Helen , Haworth Oliver , Williams John HH , Filer Andrew , Salmon Mike , Buckley Christopher D , Middleton Jim
Published: August 2010

Introduction

Monocytes/macrophages accumulate in the rheumatoid (RA) synovium where they play a central role in inflammation and joint destruction. Identification of molecules involved in their accumulation and differentiation is important to inform therapeutic strategies. This study investigated the expression and function of chemokine receptor CCR9 in the peripheral blood (PB) and synovium of RA, non-RA patients and healthy volunteers.

Methods

CCR9 expression on PB monocytes/macrophages was analysed by flow cytometry and in synovium by immunofluorescence. Chemokine receptor CCR9 mRNA expression was examined in RA and non-RA synovium, monocytes/macrophages from PB and synovial fluid (SF) of RA patients and PB of healthy donors using the reverse transcription polymerase chain reaction (RT-PCR). Monocyte differentiation and chemotaxis to chemokine ligand 25 (CCL25)/TECK were used to study CCR9 function.

Results

CCR9 was expressed by PB monocytes/macrophages in RA and healthy donors, and increased in RA. In RA and non-RA synovia, CCR9 co-localised with cluster of differentiation 14+ (CD14+) and cluster of differentiation 68+ (CD68+) macrophages, and was more abundant in RA synovium. CCR9 mRNA was detected in the synovia of all RA patients and in some non-RA controls, and monocytes/macrophages from PB and SF of RA and healthy controls. CCL25 was detected in RA and non-RA synovia where it co-localised with CD14+ and CD68+ cells. Tumour necrosis factor alpha (TNFα) increased CCR9 expression on human acute monocytic leukemia cell line THP-1 monocytic cells. CCL25 induced a stronger monocyte differentiation in RA compared to healthy donors. CCL25 induced significant chemotaxis of PB monocytes but not consistently among individuals.

Conclusions

CCR9 expression by monocytes is increased in RA. CCL25 may be involved in the differentiation of monocytes to macrophages particularly in RA.
Relationship between patient-reported disease severity in osteoarthritis and self-reported pain, function and work productivity
Authors: Sadosky Alesia B , Bushmakin Andrew G , Cappelleri Joseph C , Lionberger David R
Published: August 2010

Introduction

Understanding the relationship between patient-reported osteoarthritis (OA) severity and other patient-reported outcomes in the real-world clinical setting can provide a basis for appropriate patient management. The objective of this study was to determine how patient-reported OA severity correlates with patient-reported outcomes including pain, function and productivity.

Methods

We used the Adelphi Disease Specific Programme (DSP) for OA, a database aggregated from large, multinational, observational studies for specific chronic diseases. Data were obtained based on a 0 to 100 mm pain visual analogue scale (VAS) and a series of questions including functioning (that is, activities of daily living) and work productivity. OA severity was rated by the patients based on the question "How bad would you say your arthritis is now?" with potential responses of "mild," "moderate," and "severe." Regression models and chi-square analyses were used to evaluate the relationships between self-reported OA severity and other outcomes.

Results

Of 998 subjects in the OA DSP U.S. database, 714 (72.5%) agreed to participate. This sample was predominantly female (61.7%) with a mean age of 63.8 ± 12.9 years. Increased OA severity was associated with an older population (P < 0.05). With increasing OA severity (mild, moderate, severe), statistically significant differences (P < 0.05) were observed in increased pain VAS scores (23.5, 50.2, 70.8, respectively), lower functioning outcomes, and a higher percent of overall work impairment due to OA (17%, 37%, 48%, respectively). The increased work impairment at greater severity levels also resulted in higher costs related to lost work productivity, with annual costs due to lost productivity estimated at $6,096, $13,2510, and $17,214 per patient for self-reported mild, moderate, and severe OA, respectively (P < 0.05 for pairwise comparisons).

Conclusions

In the clinical practice setting, patient-reported OA severity was associated with other key patient-reported outcomes and thus may provide an accurate and tangible assessment of patients' perceptions of their disease. Identifying OA patients by their perceived severity level may be of benefit to patients and health-care providers when choosing treatment options aimed at reducing pain, and improving function and productivity.
Technical Advance: Function and efficacy of an α4-integrin antagonist using bioluminescence imaging to detect leukocyte trafficking in murine experimental colitis
Authors: Murphy Carola T , Moloney Gerard , MacSharry John , Haynes Andrea , Faivre Emilie , Quinlan Aoife , McLean Peter G , Lee Kevin , OˈMahony Liam , Shanahan Fergus , Melgar Silvia , Nally Kenneth
Published: August 2010

Method for in vivo bioluminescence imaging as a valuable strategy for pre-clinical evaluation of leukocyte trafficking as shown here for small molecule α4-integrin antagonists as a promising therapeutic for IBD.

Leukocyte trafficking is a therapeutic target in IBD. The integrins α4β7 and α4β1 regulate leukocyte migration into tissues and lymphoid organs. Current strategies rely on biologics, such as mAb, to inhibit leukocyte recruitment. Here we show the in vivo therapeutic effects of a small molecule α4-integrin antagonist (GSK223618A) in a leukocyte-trafficking model and a murine model of colitis. Leukocytes isolated from MLNs of transgenic β-actin-luc+ mice were injected i.v. into recipients with DSS-induced colitis. Recipient mice were orally gavaged with vehicle or an α4-integrin antagonist 1 h pre-adoptive transfer, followed by bioluminescence whole body and ex vivo organ imaging 4 h post-transfer. To confirm its therapeutic effect, the α4-integrin antagonist was given orally twice daily for 6 days to mice with DSS-induced colitis, starting on Day 3. Clinical, macroscopic, and histological signs of inflammation were assessed and gene-expression profiles analyzed. Using bioluminescence imaging, we tracked and quantified leukocyte migration to the inflamed gut and demonstrated its inhibition by a small molecule α4-integrin antagonist. Additionally, the therapeutic effect of the antagonist was confirmed in DSS-induced colitis in terms of clinical, macroscopic, and histological signs of inflammation. Gene expression analysis suggested enhancement of tissue healing in compound-treated animals. Inhibition of leukocyte trafficking using small molecule integrin antagonists is a promising alternative to large molecule biologics. Furthermore, in vivo bioluminescence imaging is a valuable strategy for preclinical evaluation of potential therapeutics that target leukocyte trafficking in inflammatory diseases.
Parathyroid Hormone Treatment Improves Pain and Fracture Healing in Adult Hypophosphatasia
Authors: Schalin-Jäntti Camilla , Mornet Etienne , Lamminen Antti , Välimäki Matti J.
Published: August 2010

Introduction: Adult hypophosphatasia (HPP) is characterized by low serum alkaline phosphatase (S-ALP) and poorly healing fractures due to ALPL gene mutations. Increased S-ALP and fracture repair were reported in two patients treated with teriparatide, PTH 1-34. The effects of full-length PTH 1-84 have not been studied.

Methods: Two 56- and 64-yr-old sisters (patients 1 and 2) with HPP and with long-standing, painful femur fractures received PTH 1-84 (Preotact, 100 μg/d sc) for 7 and 18 months, respectively. Patient 1 had another treatment 8 months later because of new femur fractures. We characterized the underlying mutation(s) and treatment effects according to S-ALP, bone markers, serum ionized calcium, plasma phosphate (P-Pi), pain, mobility, and fracture healing.

Results: Both patients were compound heterozygotes for a p.G339R and p.E191K ALPL mutation. S-ALP increased significantly, 4.9- and 6.8-fold in patient 1 and 2.7-fold in patient 2. Responses decreased at 6 months but remained higher than basal activity. Serum N-terminal propeptide of type I procollagen and urinary N-telopeptide of type I collagen increased 14- to 19-fold and 9–5-fold in patient 1, respectively, and 9- and 3-fold in patient 2. P-Pi fluctuated in patient 1 and increased in patient 2. Pain and mobility improved promptly. Fractures healed after 7–8 months of treatment in patient 1 and at 15 months in patient 2.

Conclusion: PTH 1-84 improves pain, mobility, and fracture repair in adult HPP, even after repeat treatment. Residual activity of the p.E191K ALPL gene mutation could explain why PTH can stimulate S-ALP. P-Pi concentrations may modulate the response.
The Thyroid Hormone Receptor α1 Protein Is Expressed in Embryonic Postmitotic Neurons and Persists in Most Adult Neurons
Authors: Wallis Karin , Dudazy Susi , Hogerlinden Max van , Nordström Kristina , Mittag Jens , Vennström Björn
Published: August 2010

Thyroid hormone is essential for brain development where it acts mainly through the thyroid hormone receptor α1 (TRα1) isoform. However, the potential for the hormone to act in adult neurons has remained undefined due to difficulties in reliably determining the expression pattern of TR proteins in vivo. We therefore created a mouse strain that expresses TRα1 and green fluorescent protein as a chimeric protein from the Thra locus, allowing examination of TRα1 expression during fetal and postnatal development and in the adult. Furthermore, the use of antibodies against other markers enabled identification of TRα1 expression in subtypes of neurons and during specific stages of their maturation. TRα1 expression was first detected in postmitotic cells of the cortical plate in the embryonic telencephalon and preceded the expression of the mature neuronal protein NeuN. In the cerebellum, TRα1 expression was absent in proliferating cells of the external granular layer, but switched on as the cells migrated towards the internal granular layer. In addition, TRα1 was expressed transiently in developing Purkinje cells, but not in mature cells. Glial expression was found in tanycytes in the hypothalamus and in the cerebellum. In the adult brain, TRα1 expression was detected in essentially all neurons. Our data demonstrate that thyroid hormone, unexpectedly, has the capacity to play an important role in virtually all developing and adult neurons. Because the role of TRα1 in most neuronal cell types in vivo is largely unknown, our findings suggest that novel functions for thyroid hormone remain to be identified in the brain.
Heteromultimeric TRPML channel assemblies play a crucial role in the regulation of cell viability models and starvation-induced autophagy
Authors: Zeevi David A. , Lev Shaya , Frumkin Ayala , Minke Baruch , Bach Gideon
Published: August 2010

The mucolipin (TRPML) subfamily of transient receptor potential (TRP) cation channels consists of three members that play various roles in the regulation of membrane and protein sorting along endo-lysosomal pathways. Loss-of-function mutations in TRPML1 cause the neurodegenerative lysosomal storage disorder, mucolipidosis type IV (MLIV), whereas a gain-of-function mutation in TRPML3 is principally implicated in the hearing-impaired and abnormally pigmented varitint-waddler mouse. Currently, TRPML2 is not implicated in any pathological disorder, but we have recently shown that it is a functional cation channel that physically interacts with TRPML1 and TRPML3 to potentially regulate lysosomal integrity. Here, we show that mutant TRPMLs heteromultimerize with other mutant and wild-type TRPMLs to regulate cell viability and starvation-induced autophagy, a process that mediates macromolecular and organellar turnover under cell starvation conditions. Heteromultimerization of dominant-negative TRPMLs with constitutively active TRPMLs rescues cells from the cytotoxic effects of TRPML constitutive activity. Moreover, dominant-negative TRPML1 channels, including a mutant channel directly implicated in MLIV pathology, also inhibit starvation-induced autophagy by interacting with and affecting native TRPML channel function. Collectively, our results indicate that heteromultimerization of TRPML channels plays a role in various TRPML-regulated mechanisms.
Synthesis of Novel Photochromic Calix[4]arene Ligand Bearing a Spirobenzopyran and Three Ethyl-Ester Moieties and Photocontrol of Its Alkali Metal Ion Extractability
Authors: Machitani Koji , Saeda Megumi , Nakahara Yoshio , Kimura Keiichi
Published: August 2010

A novel photochromic calix[4]arene ligand bearing a spirobenzopyran and three ethyl-ester moieties (compound 1) was synthesized, and photocontrol of its alkali metal ion extractability was studied. In the dark, compound 1 showed the largest changes of absorption spectra for Na+ among alkali metal ions. When Na+ was gradually added to the solution of compound 1, its complexation behavior was evaluated by 1H NMR, which suggests that Na+ was taken into the cavity formed by four carbonyl oxygens and four ether oxygens, and that compound 1 formed a 1:1 complex with Na+. The proton signals originating from the spirobenzopyran moiety were slightly changed by metal-ion complexation. This means that the spirobenzopyran moiety was not very close to Na+ under dark conditions. Liquid–liquid extraction experiments with alkali metal ion using compound 1 made it clear that the extractability of Na+ was enhanced under UV-light irradiation, compared with that under visible-light irradiation. This suggests that the electrostatic interaction between a phenolate anion of the merocyanine moiety generated by UV-light irradiation and Na+ promotes the extractability to some extent.
Construction of Two- or Three-Component Low Molecular Weight Gel Systems
Authors: Yamanaka Masamichi , Aoyama Ryohei
Published: August 2010

Pyridyl group-bound tris-urea 2, whose structure is similar to the tris-urea low molecular weight gelator (LMWG) 1, was synthesized. Addition of a trace amount of 2 and Pd(OAc)2 to 1 resulted in a reduction in the critical gelation concentration (CGC) in acetone. Metal–ligand interaction between Pd(OAc)2 and the pyridyl group of 2 assist the gelation. Assistance by intermolecular hydrogen bonding was also effective for gelation of acetone. An acetone gel of 1 was formed at half the value of the CGC of 1 alone by adding a trace amount of 2 and isophthalic acid. Scanning electron microscopy (SEM) measurements of these aggregates showed structural alterations caused by the additive. A mixture of 1 and a trace amount of 2 in EtOAc gave a gel. Addition of 2 was essential to form the gel, because 1 alone did not gel EtOAc. SEM measurements indicated that 2 produced extension of the fibrous aggregates.
Gandhi and the ‘struck-off’ Doctor, Thomas Richard Allinson (1858–1918)
Authors: Scott Christopher John
Published: August 2010

Gandhi visited London on several occasions. During two of these visits, when he was a law student from 1888 and again in 1914, he met Thomas Richard Allinson, a controversial doctor whose name was erased from the Medical Register in 1892. While in London studying for the bar, Gandhi was influenced in his search for a suitable vegetarian diet by the writings and personal support of Allinson. Although disagreeing profoundly with Allinson's views on birth control, he spoke up in defence of his right to hold them – probably the first time Gandhi challenged authority and an occasion which shows him as a tongue-tied young man but even then having a personal moral code that gives insight into the character of the future Mahatma. On Gandhi's further visit to England in 1914 Allinson, although no longer on the Medical Register, treated Gandhi for pleurisy, apparently partially successfully when orthodox medicine had failed.
Establishing the Golitsyn Hospital: the contribution of Professor Efrem Osipovich Mukhin (1766–1850)
Authors: Mirsky Mark B
Published: August 2010

Golitsynsky Hospital is one of the oldest Moscow clinics founded by the Russian Aristocrat Count Golitsyn in 1802. A prominent Russian surgeon and Professor at Moscow University, Efrem Mukhin became the first senior medical doctor at this hospital and played a crucial role in its development. Six hundred and eighty-eight operations were performed at Golitsynsky Hospital between 1802 and 1807 including obstetric, gynaecological, eye and ear interventions. Mukhin performed 444 operations himself. The hospital continued functioning when Napoleon's troops occupied Moscow in September 1812. The French surgeons D Larrey, Degenet and De la Fliz worked there during this period, assisted by their Russian pupils A Migachev and V Sherbakov.
Sir Edward Mellanby (1884–1955) GBE KCB FRCP FRS: nutrition scientist and medical research mandarin
Authors: Hawgood Barbara J
Published: August 2010

Edward Mellanby used the experimental method to investigate medical problems. In 1918, working at King's College for Women, London, he provided conclusive evidence that rickets is a dietary deficiency disease due to lack of a fat-soluble vitamin [D]. In Sheffield he demonstrated that cereals, in an unbalanced diet, produced rickets due to the phytic acid content reducing the availability of calcium. Mellanby became Secretary of the Medical Research Council (1933–49) but continued his research by working at weekends. In the 1930s he campaigned for the results of nutritional research to be used for the benefit of public health. During World War II he acted as a scientific adviser to the War Cabinet and had a strong influence on the food policy which maintained successfully the nutrition of the population during the shipping blockade. Mellanby was a formidable person but with sagacity he promoted new research and guided the expansion of the organization.
Relation between patient satisfaction, compliance and the clinical benefit of a teletreatment application for chronic pain
Authors: Huis in 't Veld Rianne MHA , Kosterink Stephanie M , Barbe Tom , Lindegård Agneta , Marecek Tobias , Vollenbroek-Hutten Miriam MR
Published: August 2010

We investigated the ease of use and usefulness as a measure of patient satisfaction, compliance, clinical benefit and its mutual relationships concerning a teletreatment application for chronic pain. Fifty-two subjects with neck and shoulder pain received and completed a four-week myofeedback-based teletreatment intervention. Prior to the onset of the intervention (at baseline) and immediately after the intervention they were asked to fill in questionnaires to measure discrepancies (gap scores) between expectations and experiences with the ease of use and usefulness of the treatment, as well as pain intensity and pain disability. In addition, the actual use of the system (i.e. the volume of muscle activity data available on the server) was logged. The subjects reported a significantly higher score on ease of use after the intervention compared to baseline, suggesting that the equipment was easier to use than they expected. Compliance was associated with clinical benefit. There was no significant relation between patient satisfaction and compliance. Patient satisfaction is a key indicator of how well the telemedicine treatment met expectations and compliance is important because of its association with clinical outcomes.
Comparative outcome of oesophagogastric cancer in younger patients
Authors: Mehta Samir P , Bailey Diana , Davies Nick
Published: August 2010

INTRODUCTION

The incidence of oesophageal and gastric cardia adenocarcinoma has increased rapidly over the previous two decades. There has been a rise in the number of younger patients affected, and the disease may be more aggressive and have a worse prognosis in these individuals. Current UK guidelines for urgent cancer referral focus on patients who are over 55 years. This study prospectively compares the referral times and outcome in a cohort of patients diagnosed with oesophagogastric cancer under the age of 55 years with a matched cohort over 55 of age.

PATIENTS AND METHODS

Every patient diagnosed with oesophageal, junctional or gastric cancer under the age of 55 years and every subsequent patient over the age of 55 years was accepted into this study. In all, 17 hospitals participated over a 12-month period. The following data were recorded: duration of symptoms, number of fast-track referrals, duration from GP referral to first hospital visit and stage at presentation. A survival analysis between the two groups was conducted at 2 years after the end of recruitment.

RESULTS

In total, 102 patients under the age of 55 years were diagnosed with oesophagogastric cancer during the study period. There were fewer fast-track referrals from GPs in this group compared to the over 55-year matched cases (29.4% vs 40.2%). Duration of time from GP referral to first hospital visit was significantly longer in the under 55-year group (median 14 days vs 11 days; P = 0.045 Mann-Whitney). Stage at presentation was similar between groups, but a higher proportion of patients under 55 years were offered a curative treatment plan compared to those over 55 years (P < 0.01). Survival analysis conducted at 2 years after the end of recruitment demonstrated a longer median survival in the under 55-year group (348 days vs 248 days; P = 0.03 log rank).

CONCLUSIONS

Although there was a longer referral time in patients under the age of 55 years, this had no effect on disease stage at presentation. Patients under the age of 55 years diagnosed with oesophageal or gastric cancer appear to have a better prognosis than those aged over 55 years.
Nailbed repair and patient satisfaction in children
Authors: Pearce S , Colville RJI
Published: August 2010

INTRODUCTION

We performed an audit to assess frequency of injury to the nail bed and outcomes after repair in a busy paedi-atric hand trauma clinic.

SUBJECTS AND METHODS

This retrospective study examines 46 consecutive nail bed repairs over a 6-month period. All notes were reviewed for patient demographics, details of the injury including the operation and aftercare. Telephone interviews were used to assess patient/parent satisfaction and complications.

RESULTS

The commonest mechanism of injury was trapping a finger in a door. The accident usually occurred indoors and most frequently affected the middle finger. The majority of repairs were carried out under general anaesthetic, by registrars, using absorbable synthetic sutures, within 24 h of the injury as a day-case. Outcome data with a minimum of 15 months follow-up, showed a high satisfaction rate (8.9/10) and low complication rate (7%), none of which required further surgery. There was a high failure rate of attendance in the follow-up clinic whilst the outcomes of those attending were good.

CONCLUSIONS

Outcomes and patient satisfaction were good with a low complication rate resulting in a change of practice in our unit to an ‘opt-in’ system for follow-up.
Mechanisms of recurrence of Ta/T1 bladder cancer
Authors: Bryan Richard T , Collins Stuart I , Daykin Mark C , Zeegers Maurice P , Cheng KK , Wallace D Michael A , Sole Graham M
Published: August 2010

INTRODUCTION

Bladder cancer recurrence occurs via four mechanisms - incomplete resection, tumour cell re-implantation, growth of microscopic tumours, and new tumour formation. The first two mechanisms are influenced by clinicians before and immediately after resection; the remaining mechanisms have the potential to be influenced by chemopreventive agents. However, the relative importance and timing of these mechanisms is currently unknown. Our objective was to postulate the incidence and timing of these mechanisms by investigating the location of bladder cancer recurrences over time.

PATIENTS AND METHODS

The topographical locations of tumours and their recurrences were analysed retrospectively for 169 patients newly-diagnosed with Ta/T1 bladder cancer, with median follow-up of 33.8 months. Tumours were assigned to one or more of six bladder sectors, and time to recurrence and location of recurrences were recorded.

RESULTS

Median time to first tumour recurrence was 40 months. Median times between subsequent recurrences were 6.6, 7.9, 8.0 and 6.6 months for recurrences 1 to 2, 2 to 3, 3 to 4, and 4 to 5, respectively. The risk of first tumour recurrence in any given bladder sector increased by nearly 4-fold if the primary tumour was resected from that sector (P < 0.001); this association was not significant for subsequent recurrences. The proportion of tumour recurrences in multiple bladder sectors increased from 13% for the first recurrence to 100% for recurrence seven onwards.

CONCLUSIONS

First tumour recurrence appears different to subsequent recurrences; incomplete resection and tumour cell re-implantation may dominate at this time-point. Only later does genuine new tumour formation appear to increase in importance. This has important implications for clinical trials, especially those involving chemopreventive agents.
Outpatient Clinics: Efficiency and Cost Implications
Authors: Solanki SP , Ughratdar I , Ashpole R
Published: August 2010

Patient waiting time is often the major reason for complaints about the experience of visiting outpatient clinics. Therefore, patient satisfaction with waiting time plays a crucial role in the process of health quality assurance or quality management. This combined with the implementation of the 18-week patient pathway scheme has increased pressure to improve the efficiency of secondary and tertiary healthcare systems. The smooth working of the clinic depends on skilled health and allied professionals with robust referral and imaging display systems.
BOTA – what do we do for trainees?
Authors: Simpson Claire
Published: August 2010

The British Orthopaedic Trainees Association (BOTA) has now been established for 23 years. Set up in 1987 by Richard Rawlins, the organisation has grown from the founding 45 members to include over 1,000 trainees. Orthopaedic surgeons make up one of the two largest specialties in the Royal College of Surgeons. As such, we devolved from the Association of Surgeons in Training (ASiT) so that the views of orthopaedic trainees could be represented more specifically. That said, BOTA and ASiT have excellent working ties, joining forces on specific issues such as the European Working Time Regulations.
Medical Students' Views on the Impact of The EWTR on Surgical Training
Authors: Jones K , Lund J
Published: August 2010

The introduction of the European Working Time Regulations (EWTR) in August 2009 heralded a newera of surgical training. The traditional apprenticeship form of training will be finally and completely replaced by shift work, supplemented with modern educational aids including simulators and e-learning programmes such as the Surgical Training Education Programme® (STEP®)
Acute abdominal pain following fracture of a heterotopically formed bone incorporating a prolene mesh
Authors: Nageswaran H , Dunkley A
Published: August 2010

A case is presented of severe abdominal pain around a healed scar following fracture of a heterotopically formed bone. This should be considered an unusual differential diagnosis in patients with acute pain of unknown origin who had open abdominal surgery in the past. To our knowledge, we have also reported the first case of hetertopic bone formation incorporating a prolene mesh.
Unexpected findings at diagnostic laparoscopy: caecal incarceration with concurrent appendicitis in a patient with bilateral broad ligament defects
Authors: Onida S , Lynes K , Ozdemir BA , Whitehouse PA
Published: August 2010

Internal herniations through broad ligament defects are very rare. We present the first report of the triad of broad ligament defect, internal herniation of the caecum and appendicitis. A 36-year-old woman with phocomelia presented with right iliac fossa pain and vomiting. The patient had no previous history of trauma or surgery. Abdominal ultrasound showed a small amount of free fluid. At laparoscopy, bilateral broad ligament defects were found, with herniation of the caecum and an inflamed appendix through the right-sided defect. A laparoscopic salpingo-oophorectomy was required for reduction of the herniated bowel, and an appendicectomy was performed. Broad ligament defects may be congenital or acquired. In this case, in light of the limb abnormality and absence of previous surgery, a congenital aetiology is more likely. Ultrasound scan is not reliable and, although computed tomography may be of help, a diagnostic laparoscopy is the best investigation.
Femoral sheath lipoma causing venous obstruction syndrome
Authors: Day Andrew , Thomas Paul
Published: August 2010

Lipomas are benign, encapsulated, soft-tissue tumours composed of well-differentiated adipocytes. They arise in the subcutaneous tissue typically on the back, shoulder and neck. Lipomas have been known to cause symptomatic obstruction to venous flow by compression. We report a case of venous obstruction syndrome due to a small lipoma within the femoral sheath.
Acute pancreatitis following adder bite in the UK: a case report
Authors: Pande R , Khan HN
Published: August 2010

Adder bites are common in the UK usually manifesting with localised swelling and gastrointestinal symptoms. We report a rare case of acute pancreatitis secondary to an adder bite in Wales and highlight this serious complication which was managed with standard treatment.
Ileocaecal intussusception secondary to metastatic phyllodes tumour of the breast
Authors: Morcos Basem B , Baker Bilal , Hashem Sameh A
Published: August 2010

A patient with phyllodes tumour of the breast is discussed. During follow-up, she presented with intestinal obstruction caused by ileocaecal intussusception. The cause of the intussusception was metastatic phyllodes tumour, which is a unique presentation.
’The ins and outs of abdominal pain’: a case report of a transomental internal hernia
Authors: Choong Andrew MTL , Carney Leanne , Beaconsfield Tina , Shorvon Philip J , Bhutiani Rajinder P
Published: August 2010

We present the case of a 46-year-old man admitted with acute abdominal pain with no obvious cause despite simple investigations. Further imaging revealed a rare transomental internal hernia. At exploratory laparotomy, the hernia was released, no bowel resection was required and the patient was discharged 2 days later.
Acute superior vena cava obstruction following Ivor–Lewis oesophagectomy
Authors: Hay A , Hamouda A , Bland N , Rohatgi A , Botha A
Published: August 2010

A 53 year old man developed upper body swelling, hypotension, anuria and a metabolic acidosis within 24 h following an Ivor–Lewis oesophagectomy. His co-morbidities included hypertension, hypercholesterolaemia, ischaemic heart disease and he was a smoker. He did not have radiotherapy but had received neo-adjuvant chemotherapy through an in-dwelling right subclavian central venous catheter. Azygous vein ligation during oesophagectomy resulted in acute upper body venous hypertension and signs of hypovolaemic shock which were attributed to undiagnosed thrombotic occlusion of the superior vena cava. The patient was anticoagulated and made a full recovery after a period of stay in intensive care.
Some Canadian contributions to understanding knowledge mobilisation
Authors: Cooper Amanda , Ben Levin
Published: August 2010

Knowledge mobilisation (KM) is our label for the emerging field of inquiry that seeks to strengthen connections between research, policy and practice across sectors, disciplines and countries. This paper first outlines the challenges associated with improving KM across public services. Next, it examines contributions from the health sector (findings and implications of empirical work on KM being conducted by two teams of Canadian scholars) in relation to the education sector and the broader field. Then, it outlines the Research Supporting Practice in Education (RSPE) programme (including products, events, networks and empirical studies), which attempts to increase KM in education. The paper concludes with some ideas and strategies that can be done quickly and easily to improve KM almost immediately in any organisation as well as with suggestions for further research.
Plasma Renin Activity by LC-MS/MS: Development of a Prototypical Clinical Assay Reveals a Subpopulation of Human Plasma Samples with Substantial Peptidase Activity
Authors: Bystrom Cory E , Salameh Wael , Reitz Richard , Clarke Nigel J
Published: August 2010

BACKGROUND

For management and treatment of secondary hypertension, plasma renin activity (PRA) assay is considered an essential diagnostic tool. We developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based approach to PRA offering improvements in laboratory workflow and throughput. During development, we observed a substantial number of clinical samples that have strong degradation activity toward angiotensin (Ang) I during generation. A preliminary characterization of this degradation activity was performed, and we provide here a method by which this degradation can be monitored via the addition of an isotope-labeled degradation standard.

METHODS

Automated online sample extraction coupled with HPLC was used to isolate Ang I and internal standard from plasma. The effluent from the analytical column was directed to a triple quadrupole MS operated in selected reaction monitoring mode, monitoring the a5 and b5 product ions from the [M+3H]+3 precursors. Routine analysis could be achieved with as little as 150 μL plasma.

RESULTS

We identified both C-terminal and N-terminal degradation products of Ang I using isotope-labeled peptides as controls and substrates. In 2%–5% of patient samples, the degradation essentially eliminated any Ang I produced during generation.

CONCLUSIONS

Our method requires reduced sample handling when compared with an RIA and eliminates the need for extended generation times for samples with low renin activity. Degradation of Ang I during generation appears to be a confounding variable in the interpretation of results from some clinical samples. Samples with profound degradation activity can be identified using a degradation standard that is added at the start of generation.
The Relationships Between Adaptive and Maladaptive Perfectionism and Aggression Among Turkish Adolescents
Authors: Öngen Demet Erol
Published: August 2010

The associations between adaptive/maladaptive perfectionism and different dimensions of aggression among adolescents have seldom been made the focus of empirical research. Research in this area is important as only negative conceptualisation of perfectionism, proposed within the literature, represents a limited perspective of perfectionism for adolescents. The purpose of this research was to investigate the relations between adaptive/maladaptive perfectionism and aggression in a sample of 445 Turkish high school adolescents. The Almost Perfect Scale — Revised (APS-R; Slaney, Rice, Mobley, Trippi, & Ashby, 2001) and the Buss-Perry Aggression Questionnaire (BPAQ; Buss & Perry, 1992) were used for data collection. The subdimensions of the APS-R were high standards, order (adaptive perfectionism), and discrepancy (maladaptive perfectionism). The subdimensions of the BPAQ were anger, physical aggression, hostility and verbal aggression. As hypothesised, the regression analyses revealed that, discrepancy was the positive predictor of anger, physical aggression and hostility while order was the negative predictor of anger, physical and verbal aggression. As predicted, high standards were found to be the negative predictor of hostility. However, unexpectedly, high standards were found to be the positive predictor of verbal aggression.