[Vesicovaginal fistulas: diagnosis and surgical management]. / Vesikovaginale Fisteln: Diagnostik und operatives Management.

Vesicovaginal fistulas (VVF) represent a detrimental condition causing psychological, physical and social strain on patients. In developed countries they are predominantly the result of pelvic surgery or radiation therapy, whilst obstetric VVF are common in developing countries due to prolonged and complicated births. The majority of VVF require surgical therapy, thus a comprehensive diagnostic workup is needed. Depending on diagnostic characteristics fistula repair can be performed by a transvaginal, transabdominal or minimally invasive approach. Timing of surgery, appropriate interposition of vascularized grafts, optimized postoperative management and surgical expertise are determining factors for successful treatment. This review describes the diagnostic workup and therapeutic management of VVF including various surgical techniques.

Guidance on prevention of unintended and accidental radiation exposures in nuclear medicine.

Nuclear medicine (NM) procedures for diagnosis and treatment of disease are performed routinely in hospitals throughout the world. These involve preparation and administration to patients of pharmaceuticals labelled with radioactive material. The International Atomic Energy Agency (IAEA) and the World Health Organisation highlighted the need for improvement in prevention of medical radiation incidents and accidents in the Bonn Call-for-Action in 2012. An IAEA Technical Meeting was held on prevention of unintended exposures and accidents in NM in 2018 to address the issue. Exposures can take place at any time when radioactive material is being produced and used, and the risk continues after procedures have been completed. Thus there is potential for staff or members of the general public to be exposed, as well as patients. This paper sets out guidelines for incident prevention based on presentations and discussions at the meeting, and review of reports from the literature. It deals with potential incidents in in-house radionuclide production, radiopharmaceutical preparation, administration to patients, and following a procedure, as well as aspects in management of radioactive materials. Special attention has been paid to therapeutic procedures, as these have the potential to cause more harm to patients from erroneous administrations, including tissue reactions from extravasation of radiopharmaceutical, and could lead to significant contamination events. Administration of NM therapy is generally contraindicated in pregnancy. Identification of any patient who may be pregnant is crucial and it might be necessary to verify this with a pregnancy test for patients within the age band considered to be fertile. Inclusion of NM therapy incidents in the IAEA automated reporting system SAFRON is recommended. In summary, the paper aims to highlight errors that could occur during different phases of NM procedures in order to aid prevention of incidents. The value of periodic audit in evaluating systems in place on a regular basis is emphasised. Approaches to incident investigation and follow-up are described, and the need to ensure corrective action is taken to address any deficiencies stressed.

Modeling complete removal of risk assessment questions in the USA predicts the risk of HIV exposure in blood recipients could increase despite the use of nucleic acid testing.

BACKGROUND AND OBJECTIVES: The safety of the blood supply in a number of countries is achieved by interventions that include behaviour-based time-limited or indefinite deferrals and screening of donated units for transfusion-transmitted infections. The relatively high sensitivity of nucleic acid testing (NAT) used in blood donor screening has raised the question of whether such time-based deferrals can be eliminated in favour of individual risk assessment. MATERIALS AND METHODS: Data on the annual number of incident human immunodeficiency virus (HIV) infections associated with various behaviours and on the performance characteristics of NAT applied to donor screening were used to model the number of potentially infected units that might escape detection in the worst-case scenario in which individual risk assessment was implemented, but was not effective as a screening tool, and donors did not otherwise self-select for lower risk. RESULTS: In the absence of effective individual risk-based screening or donor self-selection, the model predicts that in the United States, an additional 39 (95% CI 35-43) HIV-infected units would escape detection by nucleic acid testing, potentially capable of exposing approximately 68 (95% CI 61-75) individuals to the risk of HIV infection through the administration of prepared blood components. CONCLUSION: Despite some inherent uncertainty, the worst-case scenario of completely ineffective individual risk assessment, absence of donor self-selection and increased reliance on NAT for blood screening is estimated to be associated with an approximately fourfold increase in the risk of HIV exposure through transfusion in the United States.

Evidence of dose saving in routine CT practice using iterative reconstruction derived from a national diagnostic reference level survey.

OBJECTIVE: To assess the influence and significance of the use of iterative reconstruction (IR) algorithms on patient dose in CT in Australia. METHODS: We examined survey data submitted to the Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) National Diagnostic Reference Level Service (NDRLS) during 2013 and 2014. We compared median survey dose metrics with categorization by scan region and use of IR. RESULTS: The use of IR results in a reduction in volume CT dose index of between 17% and 44% and a reduction in dose-length product of between 14% and 34% depending on the specific scan region. The reduction was highly significant (p < 0.001, Wilcoxon rank-sum test) for all six scan regions included in the NDRLS. Overall, 69% (806/1167) of surveys included in the analysis used IR. CONCLUSION: The use of IR in CT is achieving dose savings of 20-30% in routine practice in Australia. IR appears to be widely used by participants in the ARPANSA NDRLS with approximately 70% of surveys submitted employing this technique. ADVANCES IN KNOWLEDGE: This study examines the impact of the use of IR on patient dose in CT on a national scale.

Australian per caput dose from diagnostic imaging and nuclear medicine.

The largest man-made contributor to the ionising radiation dose to the Australian population is from diagnostic imaging and nuclear medicine. The last estimation of this dose was made in 2004 (1.3 mSv), this paper describes a recent re-evaluation of this dose to reflect the changes in imaging trends and technology. The estimation was calculated by summing the dose from five modalities, computed tomography (CT), general radiography/fluoroscopy, interventional procedures, mammography and nuclear medicine. Estimates were made using Australian frequency data and dose data from a range of Australian and international sources of average effective dose values. The ionising radiation dose to the Australian population in 2010 from diagnostic imaging and nuclear medicine is estimated to be 1.7 mSv (1.11 mSv CT, 0.30 mSv general radiography/fluoroscopy, 0.17 mSv interventional procedures, 0.03 mSv mammography and 0.10 mSv nuclear medicine). This exceeds the estimate of 1.5 mSv per person from natural background and cosmic radiation.

Relapsing and remitting severe hypoglycemia due to a monoclonal anti-insulin antibody heralding a case of multiple myeloma.

CONTEXT: We report a novel case of insulin autoimmune syndrome (IAS) presenting with hypoglycemia due to production of a monoclonal anti-insulin antibody in a patient subsequently found to have multiple myeloma (MM). OBJECTIVE: The aim of the study was to describe the 5-yr clinical course of a patient with IAS and MM and to characterize the origin and function of the pathogenic antibody. METHODS: We conducted a longitudinal case history with laboratory investigations to characterize the anti-insulin antibody subtype, specificity, affinity, and origin. RESULTS: The patient presented with IAS, which worsened during treatment of hepatitis C. The patient was then discovered to have a monoclonal gammopathy that progressed to MM. Treatment of the MM induced remission of the neoplasia and IAS, which then followed a synchronized course of progression and response to therapy. An anti-insulin IgG(3)-λ that bound specifically but with low affinity to the insulin B chain (amino acids 9-30) and that was distinct from the primary MM IgG(3)-κ clone was recovered from the patient and cloned. The antibody bound insulin and showed mutations of normal affinity maturation. CONCLUSIONS: We describe a case of MM heralded by IAS, where full characterization of the pathogenic antibody revealed that the monoclonal anti-insulin antibody had originated from a self-reactive clone.

Serum non-coding RNAs as biomarkers for osteoarthritis progression after ACL injury.

OBJECTIVE: The aim of this study was to examine serum non-coding RNAs as potential biomarkers for cartilage damage associated with anterior cruciate ligament (ACL) injury. METHODS: Serum was obtained from 80 patients 1 year after surgery for ACL injury and 60 normal donors without overt skeletal injury. Total serum RNA was isolated, small non-coding RNAs profiled by TaqMan array MicroRNA (miRNA) analysis and individual small RNA assays performed by quantitative TaqMan RT-PCR (qPCR). Semi-quantitative magnetic resonance imaging (MRI) analysis was performed using Whole Organ Magnetic Resonance Knee Score (WORMS) scoring for analysis of cartilage damage. RESULTS: Initial TaqMan array miRNA profiling showed an increased serum concentration of a small nucleolar RNA (snoRNA), U48, in five patients with cartilage damage compared with that in five patients without cartilage damage and six normal donors. Independent qPCR analysis of snoRNAs in serum from all patients and normal donors showed a strong association between the serum level of another snoRNA, U38, and cartilage damage in ACL injury patients and together with snoRNA, U48, clear distinction between ACL injury patients and normal donors. CONCLUSION: SnoRNAs U38 and U48 are significantly elevated in the serum of patients developing cartilage damage at 1 year after ACL injury. Serum levels of U38 have the potential to facilitate early diagnosis of patients with cartilage damage after ACL injury. This study suggests serum non-coding RNAs may serve as novel noninvasive biomarkers for the detection and assessment of cartilage damage after ACL injury.

The effect of the sitting upright or 'beachchair' position on cerebral blood flow during anaesthesia for shoulder surgery.

The sitting upright or 'beachchair' position is commonly used for shoulder arthroscopic surgery. There is a theoretical concern that anaesthetised patients placed in this posture are at risk of reduced cerebral blood flow (CBF), especially if there is associated hypotension. This study investigated the effect of anaesthetic-induced hypotension on estimated cerebral blood flow in patients placed in the beachchair position for shoulder surgery. Forty patients were randomised to either sedation (propofol infusion 10 to 20 mg x hour 1, n = 20) or general anaesthesia using sub minimum alveolar concentration of sevoflurane (n = 20). All patients received an interscalene brachial plexus regional block. Internal carotid artery blood flow was measured using the time averaged velocity of the spectral Doppler waveform, and was then used as an estimate of global CBF. Following a pre-anaesthesia study, measurement of internal carotid artery blood flow was made before and after beachchair positioning, and at five-minute intervals during surgery. Beachchair positioning during general anaesthesia significantly decreased the mean arterial pressure (34 +/- 10 mmHg) compared to sedation (4 +/- 2 mmHg, P < 0.01), and vasopressor therapy was required more often. However, CBF remained constant in both anaesthetised (P = 0.83) and sedated patients (P = 0.68) despite beachchair positioning, and the fall in mean arterial pressure in the anaesthetised patients. There was no significant difference in CBF between groups (P = 0.91). These findings indicate that in patients in the beachchair position receiving sevoflurane anaesthesia, CBF is maintained when mean arterial pressure is above 70 mmHg, consistent with intact autoregulation.

Patterns and characteristics of hepatitis C transmission clusters among HIV-positive and HIV-negative individuals in the Australian trial in acute hepatitis C.

BACKGROUND: Injecting drug users remain the population at greatest risk of acquiring hepatitis C virus (HCV) infection, although a recent increase in cases of sexually transmitted HCV infection has been observed among human immunodeficiency virus (HIV)-infected individuals. The extent to which these separate epidemics overlap is unknown. METHODS: The Australian Trial in Acute Hepatitis C (ATAHC) enrolled 163 individuals (29% of whom were HIV infected) with recent HCV infection. E1/HVR1 sequences were used to construct phylogenetic trees demonstrating monophyletic clusters or pairs, and viral epidemic history and phylogeography were assessed using molecular clock analysis. Individual clusters were characterized by clinical and demographic characteristics. RESULTS: Transmission through injection drug use occurred for 73% of subjects, with sexual transmission occurring for 18% (92% of whom were HIV infected). Among 112 individuals with available E1/HVR1 sequences, 23 (20%) were infected with a strain of HCV identical to that of another subject, comprising 4 homologous clusters and 3 monophyletic pairs, the majority of which (78%) were HIV infected. Clusters contained individuals with both injection drug use-related and sex-related acquisition, and in all clusters (except for 1 female HIV-uninfected pair), individuals identified as men who have sex with men, irrespective of HIV status. CONCLUSIONS: This large unique study of HIV-infected and HIV-uninfected individuals with recently acquired HCV infection demonstrates that clustering is common in the HIV-infected population and that it occurred almost invariably among men who have sex with men, irrespective of the actual mode of acquisition. These findings suggest the coexistence of both injection drug use and sexual risk behaviors for individuals in the same social networks and have implications for the development of public health messages. Clinical trial registration. NCT00192569.

Ultrasound of the posterior circumflex humeral artery.

Quadrilateral space syndrome (QSS) is described as compression neuropathy of the axillary neurovascular bundle in the quadrilateral space of the shoulder. This neurovascular bundle includes the posterior circumflex humeral artery (PCHA). Historically, angiography and more recently magnetic resonance angiography have been used to assess occlusion and stenosis of the PCHA in cases of suspected QSS. These traditional imaging techniques have a number of disadvantages in terms of cost, availability, invasiveness and patient comfort. We undertook to examine the ability of ultrasound to reliably visualise the PCHA. Asymptomatic adult volunteers were recruited from staff, and patients attending the radiology department who presented for pathologies unrelated to the shoulder. We used a new technique to assess blood flow in the PCHA, performing the scan from a posterolateral approach on the upper arm just above the level of the surgical neck of the humerus. This technique enabled the scan to be undertaken with the patient seated comfortably. Fifty volunteers were recruited into the study. The mean (+/-SD) age was 35 (+/-14 years). The PCHA was visualised in all patients. Our method was able to maximise Doppler sensitivity and visualisation of the artery without discomfort to the patient in less than 10 min. Ultrasound can be used to reliably visualise the PCHA. Ultrasound has potential to be used in the assessment of the PCHA in cases of QSS.

Histone deacetylase inhibitors: Potential in cancer therapy.

The role of histone deacetylases (HDAC) and the potential of these enzymes as therapeutic targets for cancer, neurodegenerative diseases and a number of other disorders is an area of rapidly expanding investigation. There are 18 HDACs in humans. These enzymes are not redundant in function. Eleven of the HDACs are zinc dependent, classified on the basis of homology to yeast HDACs: Class I includes HDACs 1, 2, 3, and 8; Class IIA includes HDACs 4, 5, 7, and 9; Class IIB, HDACs 6 and 10; and Class IV, HDAC 11. Class III HDACs, sirtuins 1-7, have an absolute requirement for NAD(+), are not zinc dependent and generally not inhibited by compounds that inhibit zinc dependent deacetylases. In addition to histones, HDACs have many nonhistone protein substrates which have a role in regulation of gene expression, cell proliferation, cell migration, cell death, and angiogenesis. HDAC inhibitors (HDACi) have been discovered of different chemical structure. HDACi cause accumulation of acetylated forms of proteins which can alter their structure and function. HDACi can induce different phenotypes in various transformed cells, including growth arrest, apoptosis, reactive oxygen species facilitated cell death and mitotic cell death. Normal cells are relatively resistant to HDACi induced cell death. Several HDACi are in various stages of development, including clinical trials as monotherapy and in combination with other anti-cancer drugs and radiation. The first HDACi approved by the FDA for cancer therapy is suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza), approved for treatment of cutaneous T-cell lymphoma.

Quantitative MR imaging evaluation of the cartilage thickness and subchondral bone area in patients with ACL-reconstructions 7 years after surgery.

OBJECTIVE: To evaluate the cartilage thickness (ThC) and subchondral bone area (tAB) of the operated and contra-lateral non-operated (healthy) knees in patients with anterior cruciate ligament (ACL)-reconstruction 7 years after surgery using a quantitative and regional cartilage MR imaging (qMRI) technique. METHODS: Charts of 410 patients with ACL-reconstructions were retrospectively reviewed. Fifty-two patients (male/female, 28/24; mean age, 33.3 years) were included. Patients underwent KT-1000 testing and qMRI of both knees using coronal fat-saturated 3D spoiled gradient-recalled echo (SPGR) sequences (TR/TE, 44/4 ms) at 1.5 T. Quantitative analyses of ThC and tAB in the femoro-tibial cartilage plates were performed using a subregional approach. In addition, qualitative and quantitative assessment of femoral condyle shapes was performed. t tests with Bonferroni corrections were used for statistical analysis of side-to-side differences between the operated and non-operated knees. RESULTS: KT-1000 testing was abnormal in 3/52 patients (6%). Lateral femoral tAB was significantly lower (-9.2%), and medial tibial tAB was significantly larger (+2%) in the operated vs non-operated knee (P<0.001). Regional and subregional ThC side-to-side differences were less than 0.1mm and, except for the external lateral femoral subregion, they were not statistically significant. Flattened and broader shapes of medial femoral condyles (P<0.001) were found in operated knees. No significant association of presence of cartilage or meniscus lesions at surgery with ThC 7 years post-operatively was found (P=0.06-0.98). CONCLUSION: There is evidence for changes in the tAB and femoral shape 7 years post-ACL-reconstruction, but no side-to-side differences in subregional ThC were found between the operated and contra-lateral non-operated knees.

HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation.

Eighteen histone deacetylases (HDACs) are present in humans, categorized into two groups: zinc-dependent enzymes (HDAC1-11) and NAD(+)-dependent enzymes (sirtuins 1-7). Among zinc-dependent HDACs, HDAC6 is unique. It has a cytoplasmic localization, two catalytic sites, a ubiquitin-binding site, and it selectively deacetylases alpha-tubulin and Hsp90. Here, we report the discovery that the redox regulatory proteins, peroxiredoxin (Prx) I and Prx II are specific targets of HDAC6. Prx are antioxidants enzymes whose main function is H(2)O(2) reduction. Prx are elevated in many cancers and neurodegenerative diseases. The acetylated form of Prx accumulates in the absence of an active HDAC6. Acetylation of Prx increases its reducing activity, its resistance to superoxidation, and its resistance to transition to high-molecular-mass complexes. Thus, HDAC6 and Prx are targets for modulating intracellular redox status in therapeutic strategies for disorders as disparate as cancers and neurodegenerative diseases.

Histone deacetylase inhibitors: molecular mechanisms of action.

This review focuses on the mechanisms of action of histone deacetylase (HDAC) inhibitors (HDACi), a group of recently discovered 'targeted' anticancer agents. There are 18 HDACs, which are generally divided into four classes, based on sequence homology to yeast counterparts. Classical HDACi such as the hydroxamic acid-based vorinostat (also known as SAHA and Zolinza) inhibits classes I, II and IV, but not the NAD+-dependent class III enzymes. In clinical trials, vorinostat has activity against hematologic and solid cancers at doses well tolerated by patients. In addition to histones, HDACs have many other protein substrates involved in regulation of gene expression, cell proliferation and cell death. Inhibition of HDACs causes accumulation of acetylated forms of these proteins, altering their function. Thus, HDACs are more properly called 'lysine deacetylases.' HDACi induces different phenotypes in various transformed cells, including growth arrest, activation of the extrinsic and/or intrinsic apoptotic pathways, autophagic cell death, reactive oxygen species (ROS)-induced cell death, mitotic cell death and senescence. In comparison, normal cells are relatively more resistant to HDACi-induced cell death. The plurality of mechanisms of HDACi-induced cell death reflects both the multiple substrates of HDACs and the heterogeneous patterns of molecular alterations present in different cancer cells.

Trends in risk factors and etiology of 606 cases of infective endocarditis over 23 years (1984-2006) in slovakia.

The aim of this study was to assess trends in risk factors, etiology, outcome and treatment strategies for endocarditis over 23 years in Slovakia. A prospective survey of 606 cases of infective endocarditis (IE) was conducted from 1984-2006. Rheumatic fever as well as previous dental surgery showed decreasing trends within the last 23 years. Also embolic complications of IE declined along with increasing rates of surgically treated patients. No significant changes in etiology were detected apart from the fact that culture-negative endocarditis increased from 10.7% to 55.4% between 1998-2001. Surgically treated patients increased from 22.7% (1984-1990) to 50.1% (2002-2006) and mortality dramatically decreased from 26.7% (1984-1990) to 5.3% (2002-2006). Staphylococcus aureus and coagulase-negative staphylococci were the leading causes (22.4% - 48%) followed by viridans streptococci (12.2%-18.2%) were a relatively stable trend over 23 years of IE in Slovakia.

Aortic valve replacement after previous coronary artery bypass grafting: experience with a simplified approach.

AIM: Aortic valve replacement (AVR) after previous coronary artery bypass grafting (CABG), particularly in a patent left internal thoracic artery (ITA), is a challenge. Avoidance of injuring the patent graft and ensuring myocardial protection are important issues in the management of these patients. The aim of this study was to evaluate a simplified surgical approach to these reoperations. METHODS: Between January 2003 and June 2005, 19 of 287 AVRs performed at our institution were in a patient subset (mean age 70 years, range: 62-82) who received AVR after previous CABG surgery. The aortic valve gradients were between 50 and 107 mm Hg. Our operation strategy followed the KIS-principle (keep it simple): both femoral vessels were cannulated using the Seldinger technique. Only the area around the ascending aorta and the right atrium was dissected to permit x-clamping, aortotomy, and catheterization for retrograde cardioplegia and a left ventricular vent. The anterior aspect of the heart and the left side, where the ITA was embedded and patent, were left untouched and not clamped. RESULTS: The mean interval between the first and second operation was 6.5 years. Fourteen patients received biological prostheses. Four patients received an additional surgery at the time of AVR. The mean operating time was 267 min; the mean AoX-clamp time was 63 min. One patient died because of severe heart failure. In all others the postoperative course was uneventful. CONCLUSIONS: We believe that the indication for AVR in patients scheduled for CABG should be re-evaluated. In those in which Redo-surgery for new or increased valve stenosis is indicated, a simple and safe surgical option is presented.

Discovery and development of SAHA as an anticancer agent.

The path to the discovery of suberoylanilide hydroxamic acid (SAHA, vorinostat) began over three decades ago with our studies designed to understand why dimethylsulfoxide causes terminal differentiation of the virus-transformed cells, murine erythroleukemia cells. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in vivo at concentrations that have little or no toxic effects on normal cells. It was discovered that SAHA inhibits the activity of histone deacetylases (HDACs), including all 11 known human class I and class II HDACs. HDACs have many protein targets whose structure and function are altered by acetylation including histones and non-histone proteins component of transcription factors controlling gene expression and proteins that regulate cell proliferation, migration and death. SAHA is in clinical trials and has significant anticancer activity against both hematologic and solid tumors at doses well tolerated by patients. A new drug application has been approved for SAHA (vorinostat) treatment of cutaneous T-cell lymphoma.

Role of thioredoxin in the response of normal and transformed cells to histone deacetylase inhibitors.

This study examines the basis of resistance and sensitivity of normal and transformed cells to histone deacetylase inhibitor (HDACi)-induced cell death, specifically the role of caspases and thioredoxin (Trx). An important attribute of HDACis is that they induce cancer cell death at concentrations to which normal cells are relatively resistant, making them well suited for cancer therapy. The mechanism underlying this selectivity has not been understood. In this study we found that the HDACi suberoylanilide hydroxamic acid (SAHA) and MS-275, a benzamide, cause an accumulation of reactive oxygen species (ROS) and caspase activation in transformed but not normal cells. Inhibition of caspases does not block HDACi-induced cell death. These studies provide a possible mechanism that can explain why normal but not certain transformed cells are resistant to HDACi-induced cell death. The HDACi causes an increase in the level of Trx, a major reducing protein for many targets, in normal cells but not in transformed cells. The SAHA-induced increase in Trx activity in normal cells is associated with no increase in ROS accumulation. Transfection of transformed cells with Trx small interfering RNA caused a marked decrease in the level of Trx protein with an increase in ROS, a decrease in cell proliferation, and an increase in sensitivity to SAHA-induced cell death. Thus, Trx, independent of the caspase apoptotic pathway, is an important determinant of resistance of cells to HDACi-induced cell death.

A randomized trial of ultrasound-guided brachial plexus anaesthesia in upper limb surgery.

Ultrasound guidance allows real-time identification of relevant anatomy and needle position when performing brachial plexus regional anaesthesia. The aim of this investigation was to determine whether the use of surface ultrasound could improve the quality of brachial plexus anaesthesia for upper limb surgery. Forty patients were randomized to either conventional "landmark-based" plexus anaesthesia, or to an ultrasound-guided approach using a 13 mHz linear array transducer Both interscalene and axillary techniques were used. The use of ultrasound significantly improved the onset and completeness of sensory (P=0.011) and motor (P=0.002) block. Ultrasound guidance also significantly reduced (P=0.012) the incidence of paraesthesia during the performance of the blocks. Ultrasound guidance increases the quality of sensory and motor blockade in brachial plexus regional anaesthesia, and by reducing the incidence of paraesthesia during performance of the blocks, may confer greater safety.