[Adolescent idiopathic scoliosis : Guideline for practical application]. / Adoleszente idiopathische Skoliose : Leitfaden für die praktische Anwendung.

Juvenile or adolescent idiopathic scoliosis is a relatively common spinal deformity, with an incidence of more than 1 %. Early diagnosis can lead to successful therapy. In the case of pathological clinical findings, the anteroposterior X­ray of the whole spine leads the way to the correct grading, according to Cobb angle measurement. Depending on the individual risk of progression, brace treatment will be started with a Cobb angle range of 20-25°. Important predictors of therapeutic success are sufficient primary corrective power and patient compliance. COBB angles of 40-50° usually lead to the recommendation for surgery, which is performed as either anterior or posterior spinal fusion in skeletally mature adolescents, depending on the grade of the deformity according to Lenke's classification. To achieve the best possible results, it is recommended that both conservative and surgical treatments are carried out by scoliosis specialists.

[Academic clinical medicine in orthopedic and trauma surgery: which route will the next generation choose?]. / Akademische klinische Medizin in Orthopädie und Unfallchirurgie: Welchen Weg geht der Nachwuchs?

BACKGROUND: An increasing clinical pressure forces academic surgeons in Germany to decide between private life and research activities. How do those people decide and how do they develop their individual career plan? MATERIAL AND METHODS: In an e-mail survey German orthopedic and trauma surgeons were interviewed on their way of reconciliation of private life, clinical duties and research. The survey included the same questions as the previous survey and a follow-up of 66 % was achieved. RESULTS: The number of consultants in the questioned cohort increased from 44 % to 66 %. More than 80 % reported that the workload had increased which was accompanied by a more clinical orientation of research activities. When asked about personal priorities and wishes leisure time was ranked first, surgical skills, research and income followed in that order. The majority were content with the current situation and career path. CONCLUSIONS: This is the first study on occupational conditions in orthopedic and trauma surgeons in a time-line based manner. It became evident that a more clinical orientation of research is needed to match the interests of clinically engaged surgeons in orthopedics and traumatology.

Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group.

Like many other complex human disorders of unknown aetiology, autoimmune-mediated type 1 diabetes may ultimately be controlled via a therapeutic approach that combines multiple agents, each with differing modes of action. The numerous advantages of such a strategy include the ability to minimize toxicities and realize synergies to enhance and prolong efficacy. The recognition that combinations might offer far-reaching benefits, at a time when few single agents have yet proved themselves in well-powered trials, represents a significant challenge to our ability to conceive and implement rational treatment designs. As a first step in this process, the Immune Tolerance Network, in collaboration with the Juvenile Diabetes Research Foundation, convened a Type 1 Diabetes Combination Therapy Assessment Group, the recommendations of which are discussed in this Perspective paper.

Expression pattern differences between osteoarthritic chondrocytes and mesenchymal stem cells during chondrogenic differentiation.

OBJECTIVE: The use of mesenchymal stem cells (MSCs) for cartilage regeneration is hampered by lack of knowledge about the underlying molecular differences between chondrogenically stimulated chondrocytes and MSCs. The aim of this study was to evaluate differences in phenotype and gene expression between primary human chondrocytes and MSCs during chondrogenic differentiation in three-dimensional (3D) pellet culture (PC). MATERIALS AND METHODS: Chondrocytes isolated from cartilage samples obtained during total knee alloarthroplastic procedure (N=8) and MSCs, purified from bone marrow aspirates of healthy donors (N=8), were cultivated in PC under chondrogenic conditions. Immunohistology and quantitative reverse transcribing PCR (RT-PCR) were performed for chondrogenic-specific markers (i.e., Sox9, Collagen II). Global gene expression of the so-cultivated chondrocytes and MSCs was assessed by a novel approach of microarray-based pathway analysis. Refinement of data was done by hypothesis-driven gene expression omnibus (GEO) dataset comparison. Validation was performed with separate samples in transforming growth factor (TGF)ß+ or TGFß- conditions by use of quantitative real-time RT-PCR. RESULTS/CONCLUSIONS: Chondrogenic commitment of both cell types was observed. Interestingly, chondrocytes demonstrated an upregulated fatty acid/cholesterol metabolism which may give hints for future optimization of culture conditions. The novel microarray-based pathway analysis applied in this study seems suitable for the evaluation of whole-genome based array datasets in case when hypotheses can be backed with already existing GEO datasets. Future experiments should further explore the different metabolic behaviour of chondrocytes and MSC.

Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of severe central visual impairment among the elderly and is associated both with environmental factors such as smoking and with genetic factors. Here, 167 unrelated AMD patients were screened for alterations in ABCR, a gene that encodes a retinal rod photoreceptor protein and is defective in Stargardt disease, a common hereditary form of macular dystrophy. Thirteen different AMD-associated alterations, both deletions and amino acid substitutions, were found in one allele of ABCR in 26 patients (16%). Identification of ABCR alterations will permit presymptomatic testing of high-risk individuals and may lead to earlier diagnosis of AMD and to new strategies for prevention and therapy.

Aspirin resistance in South African Caucasian patients with thrombotic cerebrovascular events.

OBJECTIVE: Stroke is the second commonest cause of death in both high and low- and middle-income countries [Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. The Lancet 2006; 367:1747-57]. In South Africa, a population undergoing demographic and epidemiological transition, stroke is the third commonest cause of death [Norman R, Bradshaw D, Schneider M, Pieterse D, Groenewald P. Revised burden of disease estimates for the comparative risk factor assessment, South Africa, 2000. Cape Town: Medical Research Council. 2006]. Although aspirin remains an essential part of stroke prevention, platelet response to therapeutic doses is not uniform. Some patients exhibit aspirin resistance and develop secondary thrombotic events. We decided to determine the prevalence of aspirin resistance and/or platelet hypersensitivity, as determined by platelet aggregometry, in sixty Caucasian patients who have suffered one or more Strokes and/or Transient Ischaemic Attacks (TIAs) as compared with sixty control subjects. METHODS: Aspirin resistance was determined by platelet aggregation (>20%) to one or more of the four agonists, namely arachidonic acid (1.5 mM), adrenaline (0.05 microg/ml), collagen (0.2 microg/ml) or ADP (0.1x10(-5) M). RESULTS: Two patients demonstrated "complete aspirin resistance" (non-responder to aspirin) with resistance to arachidonic acid (high concentration) noted. Three patients demonstrated "partial aspirin resistance" (semi-responder to aspirin). One contol subject showed "complete aspirin resistance". There is a 1.67% chance of a control subject being resistant to aspirin in a general South African Caucasian population. A history of prior stroke or transient ischaemic attack was associated with a statistically significant increase in risk of aspirin resistance with an odds ratio of 5.36. CONCLUSION: These results essentially concur with those of the studied literature in showing an 8% prevalence (statistically significant) of aspirin resistance (complete and partial) in South African Caucasian patients with previous atherothrombotic cerebrovascular events i.e. CVAs and/or TIAs. The current study shows an increased prevalence of aspirin resistance in people who have had prior strokes/TIAs and raises the question whether people who have had these events are somehow predisposed to vascular events or indeed recurrent vascular events. "Aspirin resistant" patients or "poor responders" to aspirin must be considered at heightened risk of atherothrombotic events and laboratory monitoring of antiplatelet therapy may become clinically useful.

[Bone tissue engineering in clinical application : assessment of the current situation]. / Knochen-Tissue-Engineering in der klinischen Anwendung : Eine Standortbestimmung.

Treatment of severe bone defects remains a challenge in orthopaedic surgery and traumatology. Surgical techniques should provide primary stability to reach osseous integration and secondary remodeling of bone grafts and substitute materials. None of the currently available substitute materials provides osteoconduction and osteogenesis comparable to those of human allografts and autografts. To enhance osteoinductive and osteogenetic properties of these implants mesenchymal stem cells are used successfully in bone tissue engineering approaches. The aim of this report is to summarize the currently available data on bone tissue engineering and preliminary experience with a tissue engineered graft in acetabular revision surgery after loosening of a hip replacement.

Poly(A), poly(A) binding protein and the regulation of mRNA stability.

This review has focused on the possibility that interactions between mRNA sequences and the poly(A)-nucleoprotein complex play important roles in mRNA turnover. It is important to stress that additional genetic and biochemical tests are necessary to characterize how PABP interacts with mRNA in cells and to determine whether the poly(A) protection hypothesis is accurate. Moreover, there may be a significant number of mRNAs whose half-lives are independent of polyadenylation. For example, the stabilities of poly(A)-containing and deadenylated alpha 2u-globulin and interferon mRNAs are similar in microinjected oocytes. Thus, an important challenge in this field will be to analyse the complex and interactive factors that determine the half-lives of specific mRNAs.

Opinions regarding neonatal resuscitation training for the obstetric physician: a survey of neonatal and obstetric training program directors.

PURPOSE: Our goal was to garner opinions regarding neonatal resuscitation training for obstetric physicians. We sought to evaluate obstacles to neonatal resuscitation training for obstetric physicians and possible solutions for implementation challenges. MATERIALS AND METHODS: We distributed a national survey via email to all neonatal-perinatal medicine fellowship directors and obstetrics & gynecology residency program directors in the United States. This survey was designed by a consensus method. RESULTS: Ninety-eight (53%) obstetric and fifty-seven (51%) neonatal program directors responded to our surveys. Eighty-eight percent of neonatologists surveyed believe that obstetricians should be neonatal resuscitation program (NRP) certified. The majority of surveyed obstetricians (>89%) believe that obstetricians should have some neonatal resuscitation training. Eighty-six percent of obstetric residents have completed training in NRP, but only 19% of obstetric attendings are NRP certified. Major barriers to NRP training that were identified include time, lack of national requirement, lack of belief it is helpful, and cost. CONCLUSIONS: Most obstetric attendings are not NRP certified, but the majority of respondents believe that obstetric providers should have some neonatal resuscitation training. Our study demonstrates that most respondents support a modified neonatal resuscitation course for obstetric physicians.

The poly(A)-poly(A)-binding protein complex is a major determinant of mRNA stability in vitro.

Using an in vitro mRNA decay system, we investigated how poly(A) and its associated poly(A)-binding protein (PABP) affect mRNA stability. Cell extracts used in the decay reactions were depleted of functional PABP either by adding excess poly(A) competitor or by passing the extracts over a poly(A)-Sepharose column. Polyadenylated mRNAs for beta-globin, chloramphenicol acetyltransferase, and simian virus 40 virion proteins were degraded 3 to 10 times faster in reactions lacking PABP than in those containing excess PABP. The addition of purified Saccharomyces cerevisiae or human cytoplasmic PABP to PABP-depleted reactions stabilized the polyadenylated mRNAs. In contrast, the decay rates of nonpolyadenylated mRNAs were unaffected by PABP, indicating that both the poly(A) and its binding protein were required for maintaining mRNA stability. A nonspecific single-stranded binding protein from Escherichia coli did not restore stability to polyadenylated mRNA, and the stabilizing effect of PABP was inhibited by anti-PABP antibody. The poly(A) tract was the first mRNA segment to be degraded in PABP-depleted reactions, confirming that the poly(A)-PABP complex was protecting the 3' region from nucleolytic attack. These results indicate that an important function of poly(A), in conjunction with its binding protein, is to protect polyadenylated mRNAs from indiscriminate destruction by cellular nucleases. A model is proposed to explain how the stability of an mRNA could be affected by the stability of its poly(A)-PABP complex.

Immunophenotype of human melanoma cells in different metastases.

The pattern of melanoma-associated antigens (MAAs) expressed on the surface of melanoma cells in 23 metastases, 15 obtained from different patients and 8 from different metastases in two patients, was studied by immunoprecipitation and sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis using monoclonal and polyclonal melanoma antisera. Though there were differences in the MAAs expressed by each melanoma, there were marked similarities as well. No more than two melanomas had a similar pattern of MAAs. However, all melanomas expressed some MAAs, and most MAAs were commonly expressed by several melanomas. Two of the MAAs studied, with molecular weights of approximately 75,000 and 95,000 to 97,000, were particularly well represented, and at least one of these two antigens was expressed by all melanoma cells. These results suggest that complete absence of tumor-associated antigens on metastatic melanoma cells is a rare phenomenon. All melanoma lines we studied expressed at least one of a restricted number of antigens. Thus despite antigenic heterogeneity, sufficient similarity remains between different melanomas to permit specific immunotherapy to be targeted to a limited number of tumor antigens.

Simulation as a tool for improving acquisition of neonatal resuscitation skills for obstetric residents.

OBJECTIVE: Our goal was to compare the confidence, knowledge, and performance of obstetric residents taught initial neonatal resuscitation steps in a simulation-based versus lecture-based format. METHODS: Our study was a prospective randomized controlled trial of 33 obstetric residents. Baseline confidence, knowledge, and clinical skills assessments were performed. Subjects were randomized to traditional lecture (n = 14) or simulation-based (n = 19) neonatal resuscitation curriculum with a focus on initial steps. Follow-up assessments were performed at 3 and 6 months. Total confidence, knowledge, and clinical performance scores and change from baseline in these scores were calculated and compared between groups. RESULTS: Both the lecture-based and simulated-based groups demonstrated significant improvement in confidence, knowledge, and performance over time. However, compared with the lecture group, the magnitude of the mean change from baseline in performance scores was significantly greater in the simulation group at 3 months (2.9 versus 10.1; p < 0.001), but not at 6 months (7.0 versus 9.3; p = 0.11). CONCLUSIONS: Our study demonstrates the superiority of simulation in teaching obstetric residents initial neonatal resuscitation steps compared with a traditional lecture format. Skills are retained for upwards of 3-6 months. Refresher instruction by 6 months post-instruction may be beneficial.

Effect of trifluoromethyl ketone-based elastase inhibitors on neutrophil function in vitro.

Neutrophils release elastase, which is known secondarily to cause tissue damage. However, it is rapidly inactivated by the endogenous alpha1-proteinase inhibitor (alpha1Pi). Nevertheless, under pathological conditions, alpha1i is inactivated by oxidants released from neutrophils, resulting in an excess of elastase at the site of inflammation. This elastase/alpha1Pi imbalance has been implicated as a pathogenic factor in cystic fibrosis, acute respiratory distress syndrome, and emphysema. Elastase inhibitors, which do not interfere with the microbicidal activity of neutrophils and are resistant to neutrophil-released oxidants, would undoubtedly represent an important advance in the management of neutrophil-mediated tissue injury. We report that a new family of elastase inhibitors ICI200355 and ZD0892 was found to be resistant toward superoxide, hypochlorous acid, hydrogen peroxide, hydroxyl radical, and peroxynitrite mediated degradation as well as having no effect on the formation of these oxidants by activated neutrophils. More importantly, we found that these inhibitors did not interfere with the ability of human neutrophils to phagocytose and to kill Staphylococcus aureus. In conclusion, a new potent class of elastase inhibitors, while blocking the effects of neutrophil elastase, was found not to impede various physiological functions of human neutrophils, in particular the ability of these phagocytic cells to phagocytose and kill bacteria.

The relationship of the skin conductance and finger pulse amplitude components of the orienting response to season of birth in schizophrenia and depression.

Schizophrenia is said to be associated with a modest excess of winter births. We examined relations of season of birth (SOB) to the skin conductance response (SCR) and finger pulse amplitude response (FPAR) components of the orienting response (OR) in 83 schizophrenic patients, 59 depressed patients, and 81 normal controls. SCR-OR nonresponding was more prevalent among depressed patients regardless of SOB, whereas only winter-born schizophrenics showed significantly more frequent electrodermal nonresponding than controls. However, this latter relation was not confirmed with log linear analysis. No other relations of SOB to SCR-OR or FPAR-OR nonresponding were significant. Our data do not support the view that nonresponding in the SCR or FPAR components of the OR is associated with winter birth either in schizophrenia or depression.

Cerebral amyloid angiopathy manifesting as recurrent intracerebral hemorrhage.

Over a period of eight years, a normotensive woman experienced eight strokelike episodes. Computed tomographic (CT) scans obtained during each of the last seven episodes demonstrated intracerebral lobar hemorrhage. Cerebral angiography and contrast-enhanced CT scans demonstrated no underlying abnormality. Our patient had recurrent intracerebral hemorrhage (ICH) with no predisposing factors or dementia. The clinical diagnosis was primary cerebral amyloid angiopathy (CAA). Brain biopsy specimens demonstrated light microscopic and ultrastructural evidence of amyloid in cerebral arterioles. We believe that the combined clinical, CT, and ultrastructural changes in this case are unique. Recurrent ICH visualized by CT scanning has diagnostic value in CAA.

Rapid initiation of gabapentin: a randomized, controlled trial.

OBJECTIVE: To compare the tolerability of two different dose-initiation regimens of gabapentin for the adjunctive treatment of partial seizures. BACKGROUND: Patient compliance is a key feature of successful outpatient pharmacologic therapy for epilepsy, and one aspect of compliance is simplicity of initiation. By using a rapid titration rate, leading to a rapid therapeutic gabapentin dose, perhaps there could be an improvement with compliance. METHODS: Male or female patients, at least 12 years old, with a recent history of partial seizures with or without secondary generalization, were randomized to receive gabapentin (following a blinded placebo period of an undisclosed number of days) as either a Slow initiation (300 mg day 1, 600 mg day 2, then 900 mg/day) or a Rapid initiation (900 mg/day immediately following the placebo lead-in). RESULTS: Starting gabapentin therapy at an initial therapeutic dosage of 900 mg/day is well tolerated by patients with epilepsy and is as safe as initiating with a titration schedule over 3 days. Of the four most common adverse events (somnolence, dizziness, ataxia, fatigue), only one, dizziness, occurred more often in the nontitrated (Rapid initiation) group than in the titrated (Slow initiation) group. CONCLUSION: Initiation of gabapentin at 900 mg/day is as well tolerated as is a 3-day titration, except for a higher incidence of dizziness.

Synthesis and pharmacological characterization of a series of leukotriene analogues with antagonist and agonist activities.

The synthesis and biological characterization of a series of novel leukotriene antagonists and agonists are reported. All of these compounds are derivatives of (5S,6R,7Z)-5-hydroxy-6-mercapto-9-phenyl-7-nonenoic acid. One of the more potent compounds is (5S,6R,7Z)-6-[[(4-carboxy-2-methoxyphenyl)methyl]thio]-5-hydroxy-9 -(4- heptylphenyl)-7-nonenoic acid (3f). In vitro evaluation of this compound on guinea pig trachea revealed that it is a competitive antagonist of LTD4 and LTE4 with pKB values of 6.4 and 5.8, respectively. On guinea pig ileum, the pKB values obtained for it with LTD4 and E4 were both 7.2. The selectivity of 3f was shown by its lack of effect on carbachol, histamine, and barium chloride concentration-response curves in guinea pig trachea.

Nonpeptidic inhibitors of human leukocyte elastase. 6. Design of a potent, intratracheally active, pyridone-based trifluoromethyl ketone.

Further modification of the 3-amino substituent in a trifluoromethyl ketone-based series of 3-amino-6-phenylpyridin-2-ones that had been optimized for oral activity led to analogs that were potent intratracheal inhibitors in a model of HLE-induced lung damage in the hamster. The best 3-amino substituent for intratracheal activity is [4-[N-[(4-chlorophenyl)sulfonyl]-carbamoyl]phenyl]sulfonyl. At a 30 min prechallenge interval, compound 9, which incorporates this substituent, had an ED50 of approximately 2 nmol/animal and, qualitatively, afforded a very similar dose-response relationship to that found with a peptidic trifluoromethyl ketone inhibitor, ICI 200,355.

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

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

Chemically stable homocinnamyl analogues of the leukotrienes: synthesis and preliminary biological evaluation.

The synthesis and biological characterization of a series of stable leukotriene analogues (2) are reported. They are derivatives of (5S,6R,7Z)-6-peptidyl-5-hydroxy-9-phenyl-7-nonenoic acid, in which the phenyl group is variously substituted with a heptanyl, 2-heptenyl, or hexanyloxy chain (R1) and the peptide is either glutathionyl, cysteinylglycinyl, or cysteinyl. The most potent agonist is (5S,6R,7Z)-6-S-glutathionyl-5-hydroxy-9-(4-heptanylphenyl)-7 -nonenoic acid. This analogue has an EC50 value of 74.5 nM, in the presence of 1-serine borate (45 mM), on guinea pig tracheal spirals. The agonist activity of the cysteinylglycinyl- and the cysteinyl-substituted analogues was inhibited by FPL-55712. Three of the analogues were weak leukotriene antagonists in vitro on guinea pig tracheal spirals. The most potent of these was (5S,6R,7Z)-6-S-cysteinyl-5-hydroxy-9-(2-heptanylphenyl)-7-++ +nonenoic acid. At 10 microM, this analogue inhibited by 28% the contraction induced by 8 nM LTE4.