Electron cryo-microscopy (cryo-EM) has revolutionized structure determination of membrane proteins and holds great potential for structure-based drug discovery. Here we discuss the potential of cryo-EM in the rational design of therapeutics for membrane proteins compared to X-ray crystallography. We also detail recent progress in the field of drug receptors, focusing on cryo-EM of two protein families with established therapeutic value, the γ-aminobutyric acid A receptors (GABA_ARs) and G protein-coupled receptors (GPCRs). GABA_ARs are pentameric ion channels, and cryo-EM structures of physiological heteromeric receptors in a lipid environment have uncovered the molecular basis of receptor modulation by drugs such as diazepam. The structures of ten GPCR-G protein complexes from three different classes of GPCRs have now been determined by cryo-EM. These structures give detailed insights into molecular interactions with drugs, GPCR-G protein selectivity, how accessory membrane proteins alter receptor-ligand pharmacology, and the mechanism by which HIV uses GPCRs to enter host cells. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 60 is January 9, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Please see Appendix 4 for a glossary of terms.The outcome of patients with esophageal cancer is generally poor. Although multimodal therapy is standard, there is conflicting evidence regarding the addition of esophagectomy to chemoradiotherapy.

To compare the effectiveness and safety of chemoradiotherapy plus surgery with that of chemoradiotherapy alone in people with nonmetastatic esophageal carcinoma.

We performed a computerized search for relevant studies, up to Feburary 2017, on the CENTRAL, MEDLINE, and Embase databases using MeSH headings and keywords. We searched five online databases of clinical trials, handsearched conference proceedings, and screened reference lists of retrieved papers.

We included randomized controlled trials (RCTs) comparing chemoradiotherapy plus esophagectomy with chemoradiotherapy alone for localized esophageal carcinoma. We excluded RCTs comparing chemotherapy or radiotherapy alone with esophagectomy.

Two authors independently selected studies, extracted data, and assessed risk of bias and the quality of the evidence, using standardized Cochrane methodological procedures. The primary outcome was overall survival (OS), estimated with Hazard Ratio (HR). Secondary outcomes, estimated with risk ratio (RR), were local and distant progression-free survival (PFS), quality of life (QoL), treatment-related mortality and morbidity, and use of salvage procedures for dysphagia. Data were analyzed using a random effects model in Review Manager 5.3 software.

From 2667 references, we identified two randomized studies, in six reports, that included 431 participants. All participants were clinically staged to have at least T3 and/or node positive thoracic esophageal carcinoma, 93% of which was squamous cell histology. The risk of methodological bias of the included studies was low to moderate.High-quality evidence found the addition of esophagectomy had little or no difference on overall survival (HR 0.99, 95% CI 0.79 to 1.24; P = 0.92; I² = 0%; two trials). Neither study reported PFS, therefore, freedom from loco-regional relapse was used as a proxy. Moderate-quality evidence suggested that the addition of esophagectomy probably improved freedom from locoregional relapse (HR 0.55, 95% CI 0.39 to 0.76; P = 0.0004; I² = 0%; two trials), but low-quality evidence suggested it may increase the risk of treatment-related mortality (RR 5.11, 95% CI 1.74 to 15.02; P = 0.003; I² = 2%; two trials).The other pre-specified outcomes (quality of life, treatment-related toxicity, and use of salvage procedures for dysphagia) were reported by only one study, which found very low-quality evidence that use of esophagectomy was associated with reduced short-term QoL (MD 0.93, 95% CI 0.24 to 1.62), and low-quality evidence that it reduced use of salvage procedures for dysphagia (HR 0.52, 95% CI 0.36 to 0.75). Neither study compared treatment-related morbidity between treatment groups.

Based on the available evidence, the addition of esophagectomy to chemoradiotherapy in locally advanced esophageal squamous cell carcinoma, provides little or no difference on overall survival, and may be associated with higher treatment-related mortality. The addition of esophagectomy probably delays locoregional relapse, however, this end point was not well defined in the included studies. It is undetermined whether these results can be applied to the treatment of adenocarcinomas, tumors involving the distal esophagus and gastro-esophageal junction, and to people with poor response to chemoradiation.

Four preschool children (with and without disabilities), who often responded inappropriately to questions, participated in the current study. Pretest results were used to create sets of questions that the children either did or did not answer correctly (i.e., known and unknown questions). We then sequentially taught two different responses to a subset of unknown questions: (a) "I don't know" (IDK), and (b) "I don't know, please tell me" (IDKPTM). Results showed that following acquisition with the target set, both responses generalized across questions and teachers for all participants. Following IDK training, some undesirable generalization of IDK to known questions occurred for 3 participants. Training of IDKPTM with the addition of a restricted reinforcement contingency was sufficient to establish correct answers to a portion of previously unknown questions. The importance of teaching generalized responses that enable the acquisition of novel intraverbals is discussed.

BACKGROUND

The simplest conceivable example of evolving systems is RNA molecules that can replicate themselves. Since replication produces a new RNA strand complementary to a template, all templates would eventually become double-stranded and, hence, become unavailable for replication. Thus the problem of how to separate the two strands is considered a major issue for the early evolution of self-replicating RNA. One biologically plausible way to copy a double-stranded RNA is to displace a preexisting strand by a newly synthesized strand. Such copying can in principle be initiated from either the (+) or (-) strand of a double-stranded RNA. Assuming that only one of them, say (+), can act as replicase when single-stranded, strand displacement produces a new replicase if the (-) strand is the template. If, however, the (+) strand is the template, it produces a new template (but no replicase). Modern transcription exhibits extreme strand preference wherein anti-sense strands are always the template. Likewise, replication by strand displacement seems optimal if it also exhibits extreme strand preference wherein (-) strands are always the template, favoring replicase production. Here we investigate whether such strand preference can evolve in a simple RNA replicator system with strand displacement.

RESULTS

We first studied a simple mathematical model of the replicator dynamics. Our results indicated that if the system is well-mixed, there is no selective force acting upon strand preference per se. Next, we studied an individual-based simulation model to investigate the evolution of strand preference under finite diffusion. Interestingly, the results showed that selective forces "emerge" because of finite diffusion. Strikingly, the direction of the strand preference that evolves [i.e. (+) or (-) strand excess] is a complex non-monotonic function of the diffusion intensity. The mechanism underlying this behavior is elucidated. Furthermore, a speciation-like phenomenon is observed under certain conditions: two extreme replication strategies, namely replicase producers and template producers, emerge and coexist among competing replicators.

CONCLUSIONS

Finite diffusion enables the evolution of strand preference, the direction of which is a non-monotonic function of the diffusion intensity. By identifying the conditions under which strand preference evolves, this study provides an insight into how a rudimentary transcription-like pattern might have emerged in an RNA-based replicator system.

METHODS

This article was reviewed by Eugene V Koonin, Rob Kinght and István Scheuring (nominated by David H Ardell). For the full reviews, please go to the Reviewers' comments section.

BACKGROUND

Recently, several information extraction systems have been developed to retrieve relevant information out of biomedical text. However, these methods represent individual efforts. In this paper, we show that by combining different algorithms and their outcome, the results improve significantly. For this reason, CONAN has been created, a system which combines different programs and their outcome. Its methods include tagging of gene/protein names, finding interaction and mutation data, tagging of biological concepts and linking to MeSH and Gene Ontology terms.

RESULTS

In this paper, we will present data that show that combining different text-mining algorithms significantly improves the results. Not only is CONAN a full-scale approach that will ultimately cover all of PubMed/MEDLINE, we also show that this universality has no effect on quality: our system performs as well as or better than existing systems.

BACKGROUND

The LDD corpus presented is available by request to the author. The system will be available shortly. For information and updates on CONAN please visit http://www.cs.uu.nl/people/rainer/conan.html.

High background noise is an important obstacle in successful signal detection and perception of an intended acoustic signal. To overcome this problem, many animals modify their acoustic signal by increasing the repetition rate, duration, amplitude or frequency range of the signal. An alternative method to ensure successful signal reception, yet to be tested in animals, involves the use of two different types of signal, where one signal type may enhance the other in periods of high background noise. Humpback whale communication signals comprise two different types: vocal signals, and surface-generated signals such as 'breaching' or 'pectoral slapping'. We found that humpback whales gradually switched from primarily vocal to primarily surface-generated communication in increasing wind speeds and background noise levels, though kept both signal types in their repertoire. Vocal signals have the advantage of having higher information content but may have the disadvantage of loosing this information in a noisy environment. Surface-generated sounds have energy distributed over a greater frequency range and may be less likely to become confused in periods of high wind-generated noise but have less information content when compared with vocal sounds. Therefore, surface-generated sounds may improve detection or enhance the perception of vocal signals in a noisy environment.

Asymmetric cell division (ACD) is a simple and evolutionary conserved process whereby a mother divides to generate two daughter cells with distinct developmental potentials. This process can generate cell fate diversity during development. Fate asymmetry may result from the unequal segregation of molecules and/or organelles between the two daughter cells. Here, I will review how fate asymmetry is regulated in the sensory bristle lineage in Drosophila and focus on the molecular mechanisms underlying ACD of the sensory organ precursor cells (SOPs). For further resources related to this article, please visit the WIREs website.

BACKGROUND

Sexual dysfunction is a medical condition that can lead to relationship issues as well as depression and has a somatoform basis. It is estimated to affect 49 % of Brazilian women. Studies have shown that both cancer diagnosis and its surgical treatment (mastectomy) affect women psychologically and can lead to psychiatric disorders. The aim of this study was to evaluate and compare sexuality in women who underwent mastectomy alone with those who underwent breast reconstruction after mastectomy.

METHODS

This descriptive transversal study analyzed two groups of patients, one with 17 women after mastectomy alone and another with 19 women who underwent breast reconstruction post mastectomy. The patients ranged in age from 18 to 60 years old. The exclusion criteria were illiteracy; ongoing chemotherapy, radiotherapy, or psychiatric treatment; or if any surgery had been performed the previous year. All patients were from the Gynecology and Plastic Surgery Department of the Federal University of São Paulo. They voluntarily answered the FSFI (Female Sexual Function Index) questionnaire. Statistical analyses were performed using Student's t test and Pearson's coefficient, and the significance level used was p < 0.05.

RESULTS

Data showed a lower FSFI score for the mastectomy-alone group compared to the breast reconstruction group (median = 10.15 ± 2.636 and 22.44 ± 3.055, respectively; p = 0.0057). There was no relationship established between the scores and postoperative time (post, p = 0.9382; pre, p = 0.2142) or between scores and remuneration income (post, p = 0.7699; pre, p = 0.5245), stable relationship (post, p = 0.2613; pre, p = 0.5245), and age (post, p = 0.3951; pre, p = 0.8427) for both groups. Mean age has shown no significant difference (p = 0.4740; median post = 47.71 ± 2.012; medina pre = 46.69 ± 1.809).

CONCLUSIONS

An improvement in sexual function has been observed in patients who underwent breast reconstruction after mastectomy, probably as a result of better self-esteem as well as body image, both of which are affected by a mastectomy. The aesthetic results were evaluated using a questionnaire, and all the patients answered positively.

METHODS

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Imitation of actions is widespread in the animal kingdom, but the mental capacities thereby implied vary greatly according to the adaptive function of copying. Behavioral synchrony in social species has many possible benefits, including minimizing predation risk and using food resources optimally, but can be understood by the simple cognitive mechanism of response facilitation by priming. Imitation can send a social message, either one of short-term meshing or group identity. Where the imitative match is opaque, as in neonatal imitation, the correspondence problem may imply an innate system of behavior matching; but in other cases, no more than priming may be involved, although there are persistent suggestions that great ape imitation implies empathic abilities. Imitation in the service of learning new skills by following another's example can be divided into contextual imitation (when to employ a familiar action, and to what problem) and production imitation (learning of new skills by imitation). Cognitively, the former requires little more than response facilitation, whereas production imitation needs at least the ability to extract the statistical regularities of repeated action and to incorporate the result into hierarchical program construction. Among our close relatives, only the great apes show much evidence of production imitation of actions, along with the ability to selectively imitate the most rational components of what they observe. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

BACKGROUND

Men tend to have more upper body mass and fat than women, a physical characteristic that may predispose them to severe motor vehicle crash (MVC) injuries, particularly in certain body regions. This study examined MVC-related regional body injury and its association with the presence of driver obesity using both real-world data and computer crash simulation.

RESULTS

Real-world data were from the 2001 to 2005 National Automotive Sampling System Crashworthiness Data System. A total of 10,941 drivers who were aged 18 years or older involved in frontal collision crashes were eligible for the study. Sex-specific logistic regression models were developed to analyze the associations between MVC injury and the presence of driver obesity. In order to confirm the findings from real-world data, computer models of obese subjects were constructed and crash simulations were performed. According to real-world data, obese men had a substantially higher risk of injury, especially serious injury, to the upper body regions including head, face, thorax, and spine than normal weight men (all p<0.05). A U-shaped relation was found between body mass index (BMI) and serious injury in the abdominal region for both men and women (p<0.05 for both BMI and BMI(2)). In the high-BMI range, men were more likely to be seriously injured than were women for all body regions except the extremities and abdominal region (all p<0.05 for interaction between BMI and sex). The findings from the computer simulation were generally consistent with the real-world results in the present study.

CONCLUSIONS

Obese men endured a much higher risk of injury to upper body regions during MVCs. This higher risk may be attributed to differences in body shape, fat distribution, and center of gravity between obese and normal-weight subjects, and between men and women. Please see later in the article for the Editors' Summary.

OBJECTIVE

Aim of this study is to examine the 5-year follow-up results of MI PIACE PIACERMI (I like to like and please myself), a cognitive-behavioural programme intended to obtain a weight growth regulation over an extended period.

METHODS

Longitudinal observational clinical study.

METHODS

Hospital-based programme, through outpatient activities.

METHODS

Thirty-one simple obese children, 13 boys and 18 girls, 6-12 years of age on admission.

METHODS

The intervention was carried out by a multidisciplinary team (paediatrician, cognitive-behavioural psychologist, physical therapist). It employed cognitive-behavioural techniques, nutrition education, promotion of physical activity, setting a high value on free play in motion. The programme actively involves parents. The following measurements were taken on admission and at 5-year follow-up: height, weight, waist circumference, body mass index (BMI), BMI standardized (BMI-SDS), and adjusted BMI (a-BMI) as actual BMI/BMI (50th percentile)*100. Dietary habits were investigated by interview and 24-h recall. Parents completed the Family Habit Inventory and the Child Behaviour Checklist (CBCL). Motor skills were assessed by using Frostig's test.

RESULTS

The dropout rate was 35.5%. In subjects who completed the 5-year follow-up, the mean and s.d. of BMI-SDS and a-BMI were, respectively, 4.23+/-0.71 and 54.7%+/-9.0 at baseline and 2.74+/-0.85 and 43.2%+/-17.3 at the last visit. Waist circumference decreased. Family habits improved significantly. Total energy intake was significantly reduced. Emotional and social aspects of obesity-related behaviours showed positive changes. Motor skills globally improved.

CONCLUSIONS

The study provides further evidence that positive persistent results may be obtained in obese children with treatment programmes combining a lifestyle centred approach, parental involvement, nutrition education and cognitive-behavioural strategies.

The C57BL/6 mouse has been shown to develop gastric adenocarcinoma after Helicobacter felis infection. This model was used to determine whether mucin and trefoil factor (TFF) expression after infection was altered in a similar fashion to the changes seen in the protective gastric mucus layer of the human stomach after H. pylori infection. Our results indicate that this mouse model mimics many of the changes seen after human H. pylori infection, including increased expression of muc4 and muc5b and loss of muc5ac. These alterations in mucin expression occurred as early as 4 weeks postinfection, before the development of significant mucous metaplasia or gastric dysplasia. The decrease in muc5ac expression occurred only in the body of the stomach and was not secondary to the adaptive immune response to infection, because a similar decrease in expression was seen after infection of B6.Rag-1(-/-) mice, which lack B and T cells. Intriguingly, the increased expression of Muc4 and Muc5b in infected C57BL/6 mice was not seen in the infected B6.Rag-1(-/-) mice. Because B6.Rag-1(-/-) mice do not develop gastric pathology after H. felis infection, these findings point to the potential role of Muc4 and Muc5b in disease progression. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

Spliceosome-mediated RNA trans-splicing, or SMaRT, is a promising strategy to design innovative gene therapy solutions for currently intractable genetic diseases. SMaRT relies on the correction of mutations at the post-transcriptional level by modifying the mRNA sequence. To achieve this, an exogenous RNA is introduced into the target cell, usually by means of gene transfer, to induce a splice event in trans between the exogenous RNA and the target endogenous pre-mRNA. This produces a chimeric mRNA composed partly of exons of the latter, and partly of exons of the former, encoding a sequence free of mutations. The principal challenge of SMaRT technology is to achieve a reaction as complete as possible, i.e., resulting in 100% repairing of the endogenous mRNA target. The proof of concept of SMaRT feasibility has already been established in several models of genetic diseases caused by recessive mutations. In such cases, in fact, the repair of only a portion of the mutant mRNA pool may be sufficient to obtain a significant therapeutic effect. However in the case of dominant mutations, the target cell must be freed from the majority of mutant mRNA copies, requiring a highly efficient trans-splicing reaction. This likely explains why only a few examples of SMaRT approaches targeting dominant mutations are reported in the literature. In this review, we explain in details the mechanism of trans-splicing, review the different strategies that are under evaluation to lead to efficient trans-splicing, and discuss the advantages and limitations of SMaRT. WIREs RNA 2016, 7:487-498. doi: 10.1002/wrna.1347 For further resources related to this article, please visit the WIREs website.

OBJECTIVE

Controversy exists regarding optimal management of high risk localized endometrial cancer. Given that vaginal brachytherapy (VB) alone is used routinely at our institution, we retrospectively reviewed our outcomes among high risk patients defined according to the PORTEC, GOG 99, and/or Aalders randomized trials of pelvic radiation versus observation to determine if acceptable rates of locoregional control could be achieved with vaginal brachytherapy alone in this highest risk patient population.

METHODS

The Roswell Park Cancer Institute hospital tumor registry was used to identify all patients with Stage I or IIA endometrial cancer treated between January 1992 and June 2006. A total of 464 patients were identified. Of 261 patients who received post-operative RT, 225 received VB alone. Of those 225, 87 met the high risk criteria as designated by PORTEC (at least 2 of the following high risk features: age>60, Grade 3, and/or myometrial invasion>>or=Occurrences of the mathematical operator' (='were changed to 'OE'. Please check.-->50%), GOG 99 (any age with 3 high risk features: Grade 2-3, >66% myometrial invasion, and/or LVSI; age>>or=50 with 2 high risk features; or age>>or=70 with 1 high risk feature), and/or Aalders (Stage IC, Grade 3). Descriptive recurrence statistics are provided.

RESULTS

Among 87 high risk patients treated with VB alone, 36, 77, and 14 were high risk per PORTEC, GOG 99, and Aalders respectively. Forty (46%) underwent pelvic lymph node dissection. With a median follow-up of 52 months, 3 (3.4%) pelvic recurrences were observed including 1 vaginal recurrence, 1 pelvic recurrence, and 1 local recurrence involving both the vagina and pelvis. All 3 local recurrences were successfully salvaged with pelvic RT+/-surgery.

CONCLUSIONS

This represents one of the largest known series of high risk localized endometrial cancer treated with VB alone. The observed 3.4% locoregional recurrence compares favorably with the 5% locoregional recurrence noted among the highest risk patients receiving pelvic RT in the PORTEC, GOG 99, and Aalders randomized trials. In this single institution experience, the 3 local recurrences were salvaged. Based on these findings, we will continue to use VB alone in the adjuvant setting for patients with high risk localized endometrial cancer.

Fungal infections of the spine are relatively uncommon. Fungi such as Coccidioides immitis and Blastomyces dermatitidis are limited to specific geographical areas whereas cryptococcus, candida, and aspergillus are found worldwide. Candida and aspergillus are normal commensals of the body and produce disease in susceptible organisms when they gain access to the vascular system through intravenous lines, during implantation of prosthetic devices, or during surgery. For the other fungi, spinal involvement usually is the result of hematogenous or direct spread of organisms from an initial pulmonary source of infection. Involvement of the vertebral bodies can lead to vertebral compression fractures and gross deformity of the spine. Spread of infection along the anterior longitudinal ligament can lead to psoas or paravertebral abscesses. Early recognition of the disease requires a high index of suspicion, proper travel history, and a detailed physical examination. Treatment relies on the prompt institution of appropriate pharmacotherapy and constant monitoring of clinical progress. Resistance to medical therapy, spinal instability, and neurologic deficits are indications for débridement and stabilization with spinal fusion. Prognosis depends on the premorbid state of the patient, the type of fungal organism, and the timing of treatment.

METHODS

Level V (expert opinion). Please see the Guidelines for Authors for a complete description of levels of evidence.

There are logical and empirical grounds that link episodic memory and the ability to imagine future events. In some sense, both episodic memory and episodic foresight may be regarded as two sides of the same capacity to travel mentally in time. After reviewing some of the recent evidence for commonalities, I discuss limits of these parallels. There are fundamental differences between thinking about past and future events that need to be kept in clear view if we are to make progress in understanding the nature of mental time travel. The reviewed evidence suggests that mental time travel is based on a complex system selected not for accuracy about past and future per se, but for fitness benefits. Functional analyses promise to lead to fruitful avenues for future research. Copyright © 2009 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

When a learner is taught a new response, the stimuli that influence its display are often unknown. The presence or absence of these stimuli alters the probability of occurrence of the response. By identifying the stimuli influencing the probability of newly acquired responses, interventionists may program for their generalization more effectively and efficiently. This investigation describes the application of an operant methodology to assess functional relationships between responses and specific stimulus variables. Four young adults with moderate mental retardation were taught to include "please" as part of requests they made in school. Four environmental stimuli, present during training, were assessed for the controlling properties they acquired. Each of the four was assessed prior to and after training by presenting it in isolation (i.e., the other three were varied). If the presence of a single stimulus associated with training did not occasion "please," then pairs of stimuli were probed. The results revealed that single-stimulus probing occasioned responding by only 1 learner; paired-stimulus probing set the occasion for including "please" by 2 others. Control of the 4th learner's responding was lost before training was introduced, because he began including "please" in his requests during baseline. The implications of these results are discussed in terms of analyzing stimulus control and promoting stimulus generalization.

For the past three decades there has been a substantial amount of scientific evidence supporting the view that attention is necessary and sufficient for perceptual representations to become conscious (i.e., for there to be something that it is like to experience a representational perceptual state). This view, however, has been recently questioned on the basis of some alleged counterevidence. In this paper we survey some of the most important recent findings. In doing so, we have two primary goals. The first is descriptive: we provide a literature review for those seeking an understanding of the present debate. The second is editorial: we suggest that the evidence alleging dissociations between consciousness and attention is not decisive. Thus, this is an opinionated overview of the debate. By presenting our assessment, we hope to bring out both sides in the debate and to underscore that the issues here remain matters of intense controversy and ongoing investigation. Copyright © 2009 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

BACKGROUND

Endometriosis is a common gynaecological condition that frequently presents with the symptom of pain. The precise pathogenesis (mode of development) of endometriosis is unclear but it is evident that endometriosis arises by the dissemination of endometrium to ectopic sites and the subsequent establishment of deposits of ectopic endometrium. The observation that endometriosis is rarely seen in the hypo-oestrogenic (low levels of oestrogen) post-menopausal woman led to the concept of medical treatment by induction of a pseudo-menopause using Gonadotrophin Releasing Hormone Analogues (GnRHas). When administered in a non-pulsatile manner (the pituitary is normally stimulated by pulses of natural GnRH and all analogues act on the pituitary at a constant level) their use results in down regulation (switching off) of the pituitary and a hypogonadotrophic hypogonadal state (low levels of female hormones due to non stimulation of the ovary).

OBJECTIVE

To determine the effectiveness of Gonadotrophin Releasing Hormone analogues (GnRHas) in the treatment of the painful symptoms of endometriosis by comparing them with no treatment, placebo, other recognised medical treatments, and surgical interventions.

METHODS

The search strategy of the Menstrual Disorders and Subfertility review group (please see Review Group details) was used to identify all randomised trials of the use of GnRHas for the treatment of the painful symptoms of endometriosis.

METHODS

Trials were included if they were randomised, and considered the effectiveness of GnRHas in the treatment of the painful symptoms of endometriosis.

METHODS

Twenty-six studies had data appropriate for inclusion in the review. The largest group (15 studies) compared GnRHas with danazol. There are 5 studies comparing GnRHas with GnRHas plus add-back therapy, 3 comparing GnRHa with GnRHa in a different form or dose, one compares them with gestrinone, one with the combined oral contraceptive pill, and one with placebo. Data was extracted independently by two reviewers. The authors of 11 studies have been contacted to clarify missing or unclear data. Only 4 have replied to date. Data on relief of pain, change in revised American Fertility Society (rAFS) scores, and side effects was collected.

RESULTS

No difference was found between GnRHas and any of the other active comparators with respect to pain relief or reduction in endometriotic deposits. The side effect profiles of the different treatments were different, with danazol and gestrinone having more androgenic side effects, while GnRHas tend to produce more hypo-oestrogenic symptoms.

CONCLUSIONS

There is little or no difference in the effectiveness of GnRHas in comparison with other medical treatments for endometriosis. GnRHas do appear to be an effective treatment. Differences that do exist relate to side effect profiles. Side effects of GnRHas can be ameliorated by the addition of addback therapy.

BACKGROUND

Marco Esposito is the first author of two of the included studies; however, he was not involved in the quality assessment of these trials. This review is based on a Cochrane systematic review entitled 'Interventions for replacing missing teeth: antibiotics at dental implant placement to prevent complications' published in The Cochrane Library (see http://www.cochrane.org for more information). Cochrane systematic reviews are regularly updated to include new research, and in response to comments and criticisms from readers. If you wish to comment on this review, please send your comments to the Cochrane website or to Marco Esposito. The Cochrane Library should be consulted for the most recent version of the review. The results of a Cochrane Review can be interpreted differently, depending on people's perspectives and circumstances. Please consider the conclusions presented carefully. They are the opinions of the review authors, and are not necessarily shared by the Cochrane Collaboration.

OBJECTIVE

To assess the beneficial or harmful effects of systemic prophylactic antibiotics at dental implant placement versus no antibiotic/placebo administration and, if antibiotics are of benefit, to find which type, dosage and duration is the most effective.

METHODS

The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched up to 2 June 2010 for randomised controlled clinical trials (RCTs) with a follow-up of at least 3 months comparing the administration of various prophylactic antibiotic regimens versus no antibiotics to patients undergoing dental implant placement. Outcome measures were prosthesis failures, implant failures, postoperative infections and adverse events (gastrointestinal, hypersensitivity, etc.). Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two review authors. Meta-analyses were conducted.

RESULTS

Four RCTs were identified: three comparing 2 g of preoperative amoxicillin versus placebo (927 patients) and the other comparing 1 g of preoperative amoxicillin plus 500 mg four times a day for 2 days versus no antibiotics (80 patients). The meta-analyses of the four trials showed a statistically significantly higher number of patients experiencing implant failures in the group not receiving antibiotics: risk ratio=0.40 (95% confidence interval (CI) 0.19 to 0.84). The number needed to treat (NNT) to prevent one patient having an implant failure is 33 (95% CI 17-100), based on a patient implant failure rate of 5% in patients not receiving antibiotics. The other outcomes were not statistically significant, and only two minor adverse events were recorded, one in the placebo group.

CONCLUSIONS

There is some evidence suggesting that 2 g of amoxicillin given orally 1 h preoperatively significantly reduce failures of dental implants placed in ordinary conditions. No significant adverse events were reported. It might be sensible to suggest the use of a single dose of 2 g prophylactic amoxicillin prior to dental implant placement. It is still unknown whether post-operative antibiotics are beneficial, and which is the most effective antibiotic.

The mRNA expression pattern of dipeptidyl peptidase (DPP) 8 and DPP9, two DPP4 homologs, was studied previously and showed a broad tissue distribution. In this study, protein expression and activity of DPP8 and DPP9 were investigated in male reproductive tissues of different mammals. Based on specific DPP activities and inhibition profiles, the proline-selective DPP activity in the bovine and rat testis could predominantly be attributed to DPP8/9 and not to DPP4. This is in contrast to the epididymis, where most of the activity was caused by DPP4. Bovine sperm preparations had very low or undetectable DPP8/9 activity. After characterization of polyclonal antibodies specific for DPP8 or DPP9, we could localize both enzymes in seminiferous tubules of the testis. A specific staining for DPP9 was found associated with spermatozoids embedded in the epithelium, just before their release into the lumen, and in spermatids. DPP8 was localized in spermatozoids in an earlier stage of maturation. These findings help to provide insight into the physiological role of DPP4-like enzymes in the male reproductive system. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.