Gamma Knife Radiosurgery for Acromegaly

Acromegaly is debilitating disease occasionally refractory to surgical and medical treatment. Stereotactic radiosurgery, and in particular Gamma Knife surgery (GKS), has proven to be an effective noninvasive adjunct to traditional treatments, leading to disease remission in a substantial proportion of patients. Such remission holds the promise of eliminating the need for expensive medications, along with side effects, as well as sparing patients the damaging sequelae of uncontrolled acromegaly. Numerous studies of radiosurgical treatments for acromegaly have been carried out. These illustrate an overall remission rate over 40%. Morbidity from radiosurgery is infrequent but can include cranial nerve palsies and hypopituitarism. Overall, stereotactic radiosurgery is a promising therapy for patients with acromegaly and deserves further study to refine its role in the treatment of affected patients

An approach to the management of patients with residual Cushing’s disease

The evaluation and management of patients with residual Cushing’s disease is one of the more complex issues facing neurosurgeons and neuroendocrinologists in clinical practice. There is considerable controversy over several relevant issues such as the timing of the assessment of whether a patient is in remission, what biochemical parameters define remission, the most appropriate course of action to take after residual disease has been defined, etc. As a consequence of the controversies, treating physicians develop notions and fall into certain practice patterns based on evidence of varying levels, their anecdotal experiences, and information gleaned from scientific meetings. This practice pattern, we believe, constitutes the “art of medicine.” We conducted a PubMed literature search to identify manuscripts containing data relevant to Cushing’s disease, outcomes of various therapeutic modalities, and recurrences. Reference lists were used to identify additional relevant manuscripts. We focused our review on manuscripts that included reasonably large series of patients, those reflecting the experience of pituitary centers and physicians recognized as experts in the field, and those papers felt to represent seminal contributions to the literature. Furthermore, trends in the evaluation and management of relevant patients have been incorporated by the senior author who has seen and evaluated over 750 patients with documented Cushing’s syndrome over the past 18 years in clinical practice. An analysis of current evidence indicated that, despite advances in neurosurgical techniques and recent developments in adjuvant therapies, patients with residual Cushing’s disease present significant management challenges to treating physicians. In this era, however, it is indeed possible to gain control of the hypercortisolism in most patients. Despite the wide variability in research methodology designed to collect relevant data, a step-wise approach to the management of these patients can be achieved. A logical step-wise approach to the evaluation of postoperative patients with Cushing’s disease is essential. Patients with residual disease require the development of an individualized plan of management that takes into account numerous factors pertaining to status of disease, the experience of treating physicians, and available therapeutic modalities

A genome-wide association study for diabetic nephropathy genes in African Americans

A genome-wide association study was performed using the Affymetrix 6.0 chip to identify genes associated with diabetic nephropathy in African Americans. Association analysis was performed adjusting for admixture in 965 type 2 diabetic African American patients with end-stage renal disease (ESRD) and in 1029 African Americans without type 2 diabetes or kidney disease as controls. The top 724 single nucleotide polymorphisms (SNPs) with evidence of association to diabetic nephropathy were then genotyped in a replication sample of an additional 709 type 2 diabetes-ESRD patients and 690 controls. SNPs with evidence of association in both the original and replication studies were tested in additional African American cohorts consisting of 1246 patients with type 2 diabetes without kidney disease and 1216 with non-diabetic ESRD to differentiate candidate loci for type 2 diabetes-ESRD, type 2 diabetes, and/or all-cause ESRD. Twenty-five SNPs were significantly associated with type 2 diabetes-ESRD in the genome-wide association and initial replication. Although genome-wide significance with type 2 diabetes was not found for any of these 25 SNPs, several genes, including RPS12, LIMK2, and SFI1 are strong candidates for diabetic nephropathy. A combined analysis of all 2890 patients with ESRD showed significant association SNPs in LIMK2 and SFI1 suggesting that they also contribute to all-cause ESRD. Thus, our results suggest that multiple loci underlie susceptibility to kidney disease in African Americans with type 2 diabetes and some may also contribute to all-cause ESRD

Physical tests for shoulder impingements and local lesions of bursa, tendon or labrum that may accompany impingement

BackgroundImpingement is a common cause of shoulder pain. Impingement mechanisms may occur subacromially (under the coraco-acromial arch) or internally (within the shoulder joint), and a number of secondary pathologies may be associated. These include subacromial-subdeltoid bursitis (inflammation of the subacromial portion of the bursa, the subdeltoid portion, or both), tendinopathy or tears affecting the rotator cuff or the long head of biceps tendon, and glenoid labral damage. Accurate diagnosis based on physical tests would facilitate early optimisation of the clinical management approach. Most people with shoulder pain are diagnosed and managed in the primary care setting.ObjectivesTo evaluate the diagnostic accuracy of physical tests for shoulder impingements (subacromial or internal) or local lesions of bursa, rotator cuff or labrum that may accompany impingement, in people whose symptoms and/or history suggest any of these disorders.Search methodsWe searched electronic databases for primary studies in two stages. in the first stage, we searched MEDLINE, EMBASE, CINAHL, AMED and DARE (all from inception to November 2005). in the second stage, we searched MEDLINE, EMBASE and AMED(2005 to 15 February 2010). Searches were delimited to articles written in English.Selection criteriaWe considered for inclusion diagnostic test accuracy studies that directly compared the accuracy of one or more physical index tests for shoulder impingement against a reference test in any clinical setting. We considered diagnostic test accuracy studies with cross-sectional or cohort designs (retrospective or prospective), case-control studies and randomised controlled trials.Data collection and analysisTwo pairs of review authors independently performed study selection, assessed the study quality using QUADAS, and extracted data onto a purpose-designed form, noting patient characteristics (including care setting), study design, index tests and reference standard, and the diagnostic 2 x 2 table. We presented information on sensitivities and specificities with 95% confidence intervals (95% CI) for the index tests. Meta-analysis was not performed.Main resultsWe included 33 studies involving 4002 shoulders in 3852 patients. Although 28 studies were prospective, study quality was still generally poor. Mainly reflecting the use of surgery as a reference test in most studies, all but two studies were judged as not meeting the criteria for having a representative spectrum of patients. However, even these two studies only partly recruited from primary care.The target conditions assessed in the 33 studies were grouped under five main categories: subacromial or internal impingement, rotator cuff tendinopathy or tears, long head of biceps tendinopathy or tears, glenoid labral lesions and multiple undifferentiated target conditions. the majority of studies used arthroscopic surgery as the reference standard. Eight studies utilised reference standards which were potentially applicable to primary care (local anaesthesia, one study; ultrasound, three studies) or the hospital outpatient setting (magnetic resonance imaging, four studies). One study used a variety of reference standards, some applicable to primary care or the hospital outpatient setting. in two of these studies the reference standard used was acceptable for identifying the target condition, but in six it was only partially so. the studies evaluated numerous standard, modified, or combination index tests and 14 novel index tests. There were 170 target condition/index test combinations, but only six instances of any index test being performed and interpreted similarly in two studies. Only two studies of a modified empty can test for full thickness tear of the rotator cuff, and two studies of a modified anterior slide test for type II superior labrum anterior to posterior (SLAP) lesions, were clinically homogenous. Due to the limited number of studies, meta-analyses were considered inappropriate. Sensitivity and specificity estimates from each study are presented on forest plots for the 170 target condition/index test combinations grouped according to target condition.Authors' conclusionsThere is insufficient evidence upon which to base selection of physical tests for shoulder impingements, and local lesions of bursa, tendon or labrum that may accompany impingement, in primary care. the large body of literature revealed extreme diversity in the performance and interpretation of tests, which hinders synthesis of the evidence and/or clinical applicability.University of Teesside, Middlesbrough, UKDepartment of Health, UKUniv Teesside, Hlth & Social Care Inst, Middlesbrough TS1 3BA, Tees Valley, EnglandUniversidade Federal de São Paulo, Dept Orthopaed & Traumatol, São Paulo, BrazilUniv Birmingham, Birmingham, W Midlands, EnglandUniversidade Federal de São Paulo, Dept Orthopaed & Traumatol, São Paulo, BrazilWeb of Scienc

Investigating the feasibility of child mortality surveillance with postmortem tissue sampling: generating constructs and variables to strengthen validity and reliability in qualitative research

The Child Health and Mortality Prevention Surveillance (CHAMPS) network aims to generate reliable data on the causes of death among children aged <5 years using all available information, including minimally invasive tissue sampling (MITS). The sensitive nature of MITS inevitably evokes religious, cultural, and ethical questions influencing the feasibility and sustainability of CHAMPS.Due to limited behavioral studies related to child MITS, we developed an innovative qualitative methodology to determine the barriers, facilitators, and other factors that affect the implementation and sustainability of CHAMPS surveillance across 7 diverse locations in sub-Saharan Africa and South Asia. We employed a multimethod grounded theory approach and analytical structure based on culturally specific conceptual frameworks. The methodology guided data interpretation and collective analyses confirming how to define dimensions of CHAMPS feasibility within the cultural context of each site while reducing subjectivity and bias in the process of interpretation and reporting.Findings showed that the approach to gain consent to conduct the MITS procedure involves religious factors associated with timing of burial, use of certain terminology, and methods of transporting the body. Community misperceptions and uncertainties resulted in rumor surveillance and consistency in information sharing. Religious pronouncements, recognition of health priorities, attention to pregnancy, and advancement of child health facilitated community acceptability. These findings helped formulate program priorities, guided site-specific adaptations in surveillance procedures, and verified inferences drawn from CHAMPS epidemiological and formative research data. Results informed appropriate community sensitization and engagement activities for introducing and sustaining mortality surveillance, including MITS

Factors Contributing to the Biofilm-Deficient Phenotype of Staphylococcus aureus sarA Mutants

Mutation of sarA in Staphylococcus aureus results in a reduced capacity to form a biofilm, but the mechanistic basis for this remains unknown. Previous transcriptional profiling experiments identified a number of genes that are differentially expressed both in a biofilm and in a sarA mutant. This included genes involved in acid tolerance and the production of nucleolytic and proteolytic exoenzymes. Based on this we generated mutations in alsSD, nuc and sspA in the S. aureus clinical isolate UAMS-1 and its isogenic sarA mutant and assessed the impact on biofilm formation. Because expression of alsSD was increased in a biofilm but decreased in a sarA mutant, we also generated a plasmid construct that allowed expression of alsSD in a sarA mutant. Mutation of alsSD limited biofilm formation, but not to the degree observed with the corresponding sarA mutant, and restoration of alsSD expression did not restore the ability to form a biofilm. In contrast, concomitant mutation of sarA and nuc significantly enhanced biofilm formation by comparison to the sarA mutant. Although mutation of sspA had no significant impact on the ability of a sarA mutant to form a biofilm, a combination of protease inhibitors (E-64, 1-10-phenanthroline, and dichloroisocoumarin) that was shown to inhibit the production of multiple extracellular proteases without inhibiting growth was also shown to enhance the ability of a sarA mutant to form a biofilm. This effect was evident only when all three inhibitors were used concurrently. This suggests that the reduced capacity of a sarA mutant to form a biofilm involves extracellular proteases of all three classes (serine, cysteine and metalloproteases). Inclusion of protease inhibitors also enhanced biofilm formation in a sarA/nuc mutant, with the combined effect of mutating nuc and adding protease inhibitors resulting in a level of biofilm formation with the sarA mutant that approached that of the UAMS-1 parent strain. These results demonstrate that the inability of a sarA mutant to repress production of extracellular nuclease and multiple proteases have independent but cumulative effects that make a significant contribution to the biofilm-deficient phenotype of an S. aureus sarA mutant

Protease-Sensitive Conformers in Broad Spectrum of Distinct PrPSc Structures in Sporadic Creutzfeldt-Jakob Disease Are Indicator of Progression Rate

The origin, range, and structure of prions causing the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), are largely unknown. To investigate the molecular mechanism responsible for the broad phenotypic variability of sCJD, we analyzed the conformational characteristics of protease-sensitive and protease-resistant fractions of the pathogenic prion protein (PrPSc) using novel conformational methods derived from a conformation-dependent immunoassay (CDI). In 46 brains of patients homozygous for polymorphisms in the PRNP gene and exhibiting either Type 1 or Type 2 western blot pattern of the PrPSc, we identified an extensive array of PrPSc structures that differ in protease sensitivity, display of critical domains, and conformational stability. Surprisingly, in sCJD cases homozygous for methionine or valine at codon 129 of the PRNP gene, the concentration and stability of protease-sensitive conformers of PrPSc correlated with progression rate of the disease. These data indicate that sCJD brains exhibit a wide spectrum of PrPSc structural states, and accordingly argue for a broad spectrum of prion strains coding for different phenotypes. The link between disease duration, levels, and stability of protease-sensitive conformers of PrPSc suggests that these conformers play an important role in the pathogenesis of sCJD

Proteomic analysis of in vivo-assembled pre-mRNA splicing complexes expands the catalog of participating factors

Previous compositional studies of pre-mRNA processing complexes have been performed in vitro on synthetic pre-mRNAs containing a single intron. To provide a more comprehensive list of polypeptides associated with the pre-mRNA splicing apparatus, we have determined the composition of the bulk pre-mRNA processing machinery in living cells. We purified endogenous nuclear pre-mRNA processing complexes from human and chicken cells comprising the massive (>200S) supraspliceosomes (a.k.a. polyspliceosomes). As expected, RNA components include a heterogeneous mixture of pre-mRNAs and the five spliceosomal snRNAs. In addition to known pre-mRNA splicing factors, 5′ end binding factors, 3′ end processing factors, mRNA export factors, hnRNPs and other RNA binding proteins, the protein components identified by mass spectrometry include RNA adenosine deaminases and several novel factors. Intriguingly, our purified supraspliceosomes also contain a number of structural proteins, nucleoporins, chromatin remodeling factors and several novel proteins that were absent from splicing complexes assembled in vitro. These in vivo analyses bring the total number of factors associated with pre-mRNA to well over 300, and represent the most comprehensive analysis of the pre-mRNA processing machinery to date