ABSTRACT
The German population is aging in accordance with the worldwide trend; however, in comparison to most other industrial countries the number of disease-free years of life gained by patients is significantly lower in Germany. Subsequently, the number of hospitalizations and necessary surgical treatment for older and especially frail patients is significantly increasing. Several frailty scoring systems have been published with the aim of improving the assessment of the perioperative risk for these patients; however, these systems for risk assessment have not yet become clinical routine in surgery and therefore this group of frail patients remains underdiagnosed in the field of surgery. Frail patients in particular often need individualized treatment or the adaptation of standard of perioperative care. It has already been clearly shown that frail patients have a markedly higher incidence for certain risk factors (e.g. postoperative delirium, hypovolemia, pharmacological side effects and drug interactions). Additionally, malnutrition is common at the time of hospital admission in up to 70% of this patient group. If not recognized and treated accordingly all these risk factors lead to a compromised rehabilitation, higher complication rates, a prolonged length of hospital stay and a higher mortality. Special preoperative risk assessment scores, which highlight physical, psychological and social evaluation should be widely implemented in surgical departments. A standardized risk assessment embedded in evidence-based prerehabilitation programs and implemented in geriatric surgery centers can help to improve the outcome in this group of fragile patients.
Subject(s)
Frail Elderly , Frailty , Geriatric Assessment , Aged , Germany , Humans , Postoperative Complications , Rehabilitation , Risk Assessment , Risk FactorsABSTRACT
BACKGROUND: The number of organ donations in Germany decreased by 32.3% between 2010 and 2017. For this reason, more than 1500 fewer organ transplantations were performed in 2017 than in 2010. QUESTION: What are the causes of this development? METHODS: Analysis of available statistics and scientific publications. RESULTS: A decline of the organ donation potential can be ruled out as the cause of the declining organ donation figures, since the number of patients who were eligible for organ donation from a medical point of view increased during the period under consideration. Similarly, there is no indication that a change in the population's attitude towards organ donation can be held responsible for this development. The decline is rather due to a recognition and reporting deficit of potential organ donors. The extent of this deficit differs considerably between different hospitals and is not only responsible for the decline in the donor rate in recent years, but also for the low donor numbers in Germany by international standards. CONCLUSION: The low organ donation figures in Germany are due to a recognition and reporting deficit. The number of organ donations could be considerably increased by improving the internal processes in hospitals.
Subject(s)
Tissue Donors , Tissue and Organ Procurement/statistics & numerical data , Germany , HumansABSTRACT
BACKGROUND: Since 2014, expected graft and recipient survival are matched by the U.S. kidney allocation system to improve organ utility. This mechanism is based on the kidney donor profile index (KDPI) and the estimated posttransplant survival score (EPTS). Here we analyzed 1. the transferability of these scores into the Eurotransplant (ET) region and 2. the extent to which the ET kidney allocation algorithm promotes utility. METHODS: We studied data of 262 kidney transplantations performed at the University Hospital Kiel between 2000 and 2009 (median follow-up, 9.94 years). RESULTS: Multivariable Cox regression analysis revealed that only the variables donor age of the KDPI and recipient's age of the EPTS have a significant value as predictors of posttransplant graft and recipient survival. The other variables showed no additional predictive value. Analyzing all kidneys allocated in the ET kidney allocation system and the European Senior Program, we found that donor and recipient's age and KDPI and EPTS were weakly correlated (rage-age = 0.5, P < .001; rKDPI-EPTS = 0.4, P < .01). If both programs were analyzed separately, no correlation between donor and recipient's age and between KDPI and EPTS was detected. CONCLUSION: The ET kidney allocation algorithm poorly matched predicted graft and recipient survival at our center. A better age-matching may improve organ utility.
Subject(s)
Algorithms , Donor Selection/methods , Kidney Transplantation , Tissue Donors/supply & distribution , Adult , Aged , Europe , Female , Graft Survival , Humans , Kidney Transplantation/mortality , Male , Middle Aged , United StatesABSTRACT
Urinary lipidomics may add new valuable biomarkers to the diagnostic armamentarium for early detection of metabolic and kidney diseases. Sources and composition of urinary lipids in healthy individuals, however, have not been investigated in detail. Shotgun lipidomics was used to quantify lipidomic profiles in native urine samples from 16 individuals (eight men, eight women) collected in five fractions over 24 h. All probands were comprehensively characterized by urinary and clinical indices. The mean total urinary lipid concentration per sample was 0.84 µM in men and 1.03 µM in women. We observed significant intra- and interindividual variations of lipid concentrations over time, but failed to detect a clear circadian pattern. Based on quantity and subclass composition it seems very unlikely that plasma serves as major source for the urinary lipidome. Considering lipid metabolites occurring in at least 20% of all samples 38 lipid species from 7 lipid classes were identified. Four phosphatidylserine and one phosphatidylethanolamine ether species (PE-O 36:5) were detectable in almost all urine samples. Sexual dimorphism has been found mainly for phosphatidylcholines and phosphatidylethanolamines. In men and in women urinary lipid species were highly correlated with urinary creatinine and albumin excretion, reflecting glomerular filtration and tubular transport processes. In women, however, lipid species deriving from urinary cells and cellular constituents of the lower genitourinary tract considerably contributed to the urinary lipidome. In conclusion, our study revealed the potential of urinary lipidomics but also the complexity of methodological challenges which have to be overcome for its implementation as a routine diagnostic tool for renal, urological and metabolic diseases.
Subject(s)
Lipid Metabolism/physiology , Lipids/urine , Sex Characteristics , Adult , Female , Healthy Volunteers , Humans , Male , Middle Aged , Phosphatidylcholines/urine , Phosphatidylethanolamines/urineABSTRACT
Following fertilization in mammals, it is generally accepted that totipotent cells are exclusive to the zygote and to each of the two blastomeres originating from the first mitotic division. This model of totipotency was inferred from a minority of cases in which blastomeres produced monozygotic twins in mice. Was this due to experimental limitation or biological constraint? Here we removed experimental obstacles and achieved reliable quantification of the prevalence of dual totipotency among mouse two-cell stage blastomeres. We separated the blastomeres of 1,252 two-cell embryos, preserving 1,210 of the pairs. Two classes of monozygotic twins became apparent at the blastocyst stage: 27% formed a functional epiblast in both members (concordant), and 73% did so in only one member of the pair (discordant) - a partition that proved insensitive to oocyte quality, sperm-entry point, culture environment and pattern of cleavage. In intact two-cell embryos, the ability of sister blastomeres to generate epiblast was also skewed. Class discovery clustering of the individual blastomeres' and blastocysts' transcriptomes points to an innate origin of concordance and discordance rather than developmental acquisition. Our data place constraints on the commonly accepted idea that totipotency is allocated equally between the two-cell stage blastomeres in mice.
Subject(s)
Blastocyst/cytology , Blastomeres/cytology , Embryo, Mammalian , Animals , Biomarkers , Blastocyst/metabolism , Blastomeres/metabolism , Embryonic Development , Gene Expression Profiling , Mice , Mitosis , Oocytes , Transcriptome , Twins, Monozygotic , ZygoteABSTRACT
The transport of intense ion beams is affected by the collective behavior of this kind of multi-particle and multi-species system. The space charge expressed by the generalized perveance dominates the dynamical process of thermalisation, which leads to emittance growth. To prevent changes of intrinsic beam properties and to reduce the intensity dependent focusing forces, space charge compensation seems to be an adequate solution. In the case of positively charged ion beams, electrons produced by residual gas ionization and secondary electrons provide the space charge compensation. The influence of the compensation particles on the beam transport and the local degree of space charge compensation is given by different beam properties as well as the ion beam optics. Especially for highly charged ion beams, space charge compensation in combination with poor vacuum conditions leads to recombination processes and therefore increased beam losses. Strategies for providing a compensation-electron reservoir at very low residual gas pressures will be discussed.
ABSTRACT
This study analyses new information on gene mutations in paragangliomas and puts them into a clinical context. A suspicion of malignancy is critical to determine the workup and surgical approach in adrenal (A-PGL) and extra-adrenal (E-PGL) paragangliomas (PGLs). Malignancy rates vary with location, family history, and gene tests results. Currently there is no algorithm incorporating the above information for clinical use. A sum of 1,821 articles were retrieved from PubMed using the search terms "paraganglioma genetics". Thirty-seven articles were selected of which 9 were analyzed. It was found that 599/2,487 (24%) patients affected with paragangliomas had a germline mutation. Of these 30.2% were mutations in SDHB, 25% VHL, 19.4% RET, 18.4% SDHD, 5.0% NF1, and 2.0% SDHC genes. A family history was positive in 18.1-64.3% of patients. Adrenal PGLs accounted for 55.1% in mutation (+) and 81.0% in mutation (-) patients (RR 1.2, p < 0.0001). Bilateral A-PGLs accounted for 56.4% in mutation (+) and 3.2% in mutation (-) patients (RR 8.7, p < 0.0001). E-PGL were found in 33.6% of mut+ and 17.3% of mut- (RR 1.7, p < 0.0001). In mutation (+) patients PGLs malignancy varied with location, adrenal (6.4%) thoraco-abdominal E-PGL (38%), H & N E-PGL (10%). Malignancy rates were 8.2% in mutation (-) and lower in mutation (+) PGLs except for SDHB 36.5% and SDHC 8.3%. Exclusion of a mutation lowered the probability of malignancy significantly in E-PGL (RR 0.03 (95% CI 0.1-0.6); p < 0.001). Mutation analysis provides valuable preoperative information to assess the risk of malignancy in A-PG and E-PGLs and should be considered in the work up of all E-PGL lesions.
Subject(s)
Genetic Predisposition to Disease , Paraganglioma/genetics , Paraganglioma/pathology , Family , Humans , Mutation/genetics , Mutation RateABSTRACT
Clinical research on penetrating injury to the buttock is sparse and largely limited to case reports and clinical series. The purpose of this paper is to provide a detailed overview of literature of the topic and to propose a basic algorithm for management of penetrating gluteal injuries (PGI). MEDLINE, EMBASE, Cochran, and CINAHL databases were employed. Thirty-seven papers were selected and retrieved for overview from 1,021 records. PGI accounts for 2-3 % of all penetrating injuries, with a mortality rate up to 4 %. Most haemodynamically stable patients will benefit from traditional wound care and selective non-operative management. When gluteal fascia injury is confirmed or suspected, a contrast-enhanced CT-scan provides the most accurate injury diagnosis. CT-scan-based angiography and endovascular interventions radically supplement assessment and management of patients with penetrating injury to the major buttock and adjacent extra-buttock arteries. Immediate life-saving damage-control surgery is indicated for patients with hypovolemic shock and signs of internal bleeding. A universal basic management algorithm is proposed. This overview shows that penetrating injury to the buttock should be regarded as a potential life-threatening injury, and therefore, patients with such injuries should be managed in trauma centres equipped with hybrid operating theatres for emergency endovascular and open surgery for multidisciplinary teams operating 24/7.
Subject(s)
Buttocks/injuries , Disease Management , Wounds, Penetrating , Diagnostic Imaging , Global Health , Humans , Incidence , Trauma Centers , Wounds, Penetrating/diagnosis , Wounds, Penetrating/epidemiology , Wounds, Penetrating/therapyABSTRACT
BACKGROUND: Parathyroid cancer has a poor mid-term prognosis, often because of local recurrence, observed in half of all patients. Modern diagnostic workup increasingly enables a preoperative diagnosis of parathyroid cancer. There is limited evidence that more comprehensive oncologic surgery can reduce the risk of local recurrence. This study aims to identify the best specific surgical approach in parathyroid cancer. METHODS: This observational cohort study comprises 19 consecutive patients who had undergone oncologic or nononcologic resection for parathyroid cancer. Baseline parameters were compared by using univariate analysis; outcomes were assessed by χ (2) testing and Kaplan-Meier statistics. RESULTS: Fifteen of 19 patients were primarily operated on in our tertiary center between 1996 and 2013, and four were referred for follow-up because of their cancer diagnosis. Patient cohorts defined by histologic R-status were comparable for established risk factors: sex, calcium levels, low-risk/high-risk status, and presence of vascular invasion. Oncologic resections were performed in 13 of 15 patients primarily treated in the center and 0 of 4 treated elsewhere (χ (2) = 5.6; p < 0.01). R0 margins were achieved in 11 of 13 (85 %) undergoing oncologic resection and 1 of 6 (17 %) undergoing local excision (χ (2) = 8.1; p < 0.01). R0 margins and primary oncologic resection were associated with higher disease-free survival rates (χ (2) = 7.9; p = 0.005 and χ (2) = 4.7; p = 0.03, respectively). Revision surgery achieved R0 margins in only 2 of 4 (50 %) of patients. CONCLUSIONS: In parathyroid cancer, a more comprehensive surgery (primary oncologic resection) provides significantly better outcomes than local excision as a result of reduction of R1 margins and locoregional recurrence.
Subject(s)
Neck Dissection , Neoplasm Recurrence, Local , Parathyroid Neoplasms/mortality , Parathyroid Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm, Residual , Reoperation , Retrospective StudiesABSTRACT
Phaeochromocytoma [corrected] crisis is an endocrine emergency associated with significant mortality. There is little published guidance on the management of phaeochromocytoma [corrected] crisis. This clinical practice update summarizes the relevant published literature, including a detailed review of cases published in the past 5 years, and a proposed classification system. We review the recommended management of phaeochromocytoma [corrected] crisis including the use of alpha-blockade, which is strongly associated with survival of a crisis. Mechanical circulatory supportive therapy (including intra-aortic balloon pump or extra-corporeal membrane oxygenation) is strongly recommended for patients with sustained hypotension. Surgical intervention should be deferred until medical stabilization is achieved.
Subject(s)
Adrenal Gland Neoplasms/drug therapy , Adrenergic alpha-Antagonists/therapeutic use , Pheochromocytoma/drug therapy , Adrenal Gland Neoplasms/physiopathology , Humans , Pheochromocytoma/physiopathology , Treatment OutcomeABSTRACT
Bariatric surgery is a well-established approach to improve metabolic disease in morbidly obese patients with high cardiovascular risk. The post-operative normalization of lipid metabolism has a central role in the prevention of future cardiovascular events. The aim of the present study therefore was to characterize changes of plasma lipidomic patterns, consisting of 229 lipid species of 13 lipid classes, 3 months after Roux-en-Y gastric bypass (RYGB) in morbidly obese patients with and without diabetes. RYGB resulted in a 15-32% decrease of body mass index, which was associated with a significant reduction of total cholesterol (TC, -28.3%; P=0.02), LDL-cholesterol (LDL-C, -26.8%; P=0.03) and triglycerides (TGs, -63.0%; P=0.05) measured by routine clinical chemistry. HDL-cholesterol remained unchanged. The effect of RYGB on the plasma lipidomic profile was characterized by significant decreases of 87 lipid species from triacylglycerides (TAGs), cholesterol esters (CholEs), lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), phosphatidylethanolamine ethers (PEOs), phosphatidylinositols (PIs) and ceramides (Cers). The total of plasma lipid components exhibited a substantial decline of 32.6% and 66 lipid species showed a decrease by over 50%. A direct correlation with HbA1C values could be demonstrated for 24 individual lipid species (10 TAG, three CholE, two LPC, one lysophosphatidylcholine ethers (LPCO) (LPC ether), one PC, two phosphatidylcholine ethers (PCO) and five Cer). Notably, two lipid species (TAG 58:5 and PEO 40:5) were inversely correlated with HbA1C. LPCO, as single whole lipid class, was directly related to HbA1C. These data indicate that RYGB-induced modulation of lipidomic profiles provides important information about post-operative metabolic adaptations and might substantially contribute to improvements of glycemic control. These striking changes in the human plasma lipidome may explain acute, weight independent and long-term effects of RYGB on the cardiovascular system, mental status and immune regulation.
Subject(s)
Diabetes Mellitus, Type 2/blood , Gastric Bypass , Lipids/blood , Obesity, Morbid/surgery , Chromatography, High Pressure Liquid , Diabetes Mellitus, Type 2/complications , Humans , Lipids/classification , Obesity, Morbid/blood , Obesity, Morbid/complicationsABSTRACT
AIM: The management of progressive peripheral artery disease experienced a vast change in paradigms over the last decades for the benefit of minimal invasive therapy as a first-line strategy. With the constant development of new devices, materials and dedicated access strategies, more complex lesions can be managed but the limitations to successfully treat chronic total occlusions are still the challenge to re-enter the true lumen. The aim of this retrospective study was to investigate, if a "wire only" strategy leads to an acceptable success rate in a mixed cohort of CTO lesions and to what extend re-entry devices are used. METHODS: We retrospectively analyzed patients treated at the Vascular Center Berlin between 2011 and 2013 with chronic total occlusion out of a prospective conducted database (Endovascular MILestones - EMIL) for demographics, risk factors, co-morbidities, technical success rates, lesion characteristics and use of guidewires as well as re-entry systems. A total of 128 patients with 146 lesions, which represent a subgroup of all the cases performed in our center, following a predefined treatment algorithm for chronic total occlusions (CTOs), have been analyzed. RESULTS: We achieved a technical success in 133 (91.1%) of all cases following a "wire only" strategy. Out of 13 (8.9%) CTOs with technical failure in 7 (53.9%) CTOs a re-entry device (Off-Road®) with a 100% technical success has been used. In 91.1% of chronic total occlusion lesions the use of 2 wires only (88.7%) led to a successful recanalization. A "wire only" strategy followed by the use of a re-entry device as a bail out strategy, led to a total of 140 (96%) lesions to be successfully recanalized. CONCLUSION: In more than 90% of all cases with chronic total occlusion of peripheral lower extremity arteries, endovascular intervention has been successful following a "wire only" strategy. When deciding to use a re-entry device, in case of a failure of a proper wire re-entry at the reconstitution point, a technical success rate of 100% was achieved. Therefore following a strict wire algorithm and considering the use of a re-entry system as a bail out strategy will lead to a successful minimal invasive management of chronic total occlusion in nearly 100% of the cases with TASC II A - D lesions.
Subject(s)
Angioplasty, Balloon/instrumentation , Lower Extremity/blood supply , Peripheral Arterial Disease/therapy , Vascular Access Devices , Adult , Aged , Angioplasty, Balloon/adverse effects , Berlin , Chronic Disease , Constriction, Pathologic , Equipment Design , Female , Humans , Male , Middle Aged , Peripheral Arterial Disease/diagnosis , Retrospective Studies , Time Factors , Treatment OutcomeABSTRACT
Legislation for people with disabilities has also changed due to other changes in the law, especially due to the recent ratification of the UN Convention on the Rights of Persons with Disabilities. These laws, in particular the UN Convention on the Rights of Persons with Disabilities, with its inclusion of the right to equitable and universal access to education for people with disabilities and their implementation, are of central importance for students who are impaired. As part of the GINKO (the legislative effect laws have on the professional integration of those who are hard of hearing, people who have gone deaf and those who are deaf through communication and organization; promotion: BMAS) project, the following questions were also brought up for discussion and were investigated: to what extent hearing-impaired students are aware of legislation that benefits them, whether these laws will be implemented, and what factors have an impact on this legal knowledge or its implementation. Overall, 4,825 handicapped individuals with hearing impairments - including n=166 students - took part in the survey. The results of the evaluation of the group of hearing-impaired students indicate that many of them are not informed about laws important to them. It was also found that the knowledge of a law cannot be equated with its implementation. This survey also resulted in a resolve for the future, to demand information about legal options be reinforced, and to adjust this information to fit the needs of specific target groups, e.g. this information could be disseminated through sign language films. On the other hand, these results also apply to higher education, for these institutions to create learning conditions where existing regulatory design options for students with disabilities are implemented, thereby affording students an equal opportunity to participate in higher education.
Subject(s)
Civil Rights , Health Knowledge, Attitudes, Practice , Patient Rights , Persons With Hearing Impairments/legislation & jurisprudence , Persons With Hearing Impairments/statistics & numerical data , Students/statistics & numerical data , Adolescent , Adult , Female , Germany , Humans , Legislation as Topic , Male , Young AdultABSTRACT
A 73-year-old man, in whom 26 years ago a malignant melanoma with cervical lymph node metastases of the right retroauricular region was diagnosed, developed BRAF V600E-negative distant metastases, which progressed during both monochemotherapy and polychemotherapy. Therefore he was started on ipilimumab in a dose of 3 mg/kg body weight four times in intervals of 3 weeks. Subsequently, there was an almost complete regression of distant metastases. In several phase III trials a significant survival benefit has been identified for patients treated with ipilimumab. The human monoclonal antibody has been approved since July 2011 as a second-line treatment in Germany and was incorporated in January 2013 into the new guidelines for the treatment of malignant melanoma. The CTLA-4 antibody is the first drug that can improve significantly survival in patients with metastatic melanoma. In advanced (unresectable or metastatic) melanoma, immunostimulatory treatment with ipilimumab represents a new therapeutic option.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Melanoma/drug therapy , Melanoma/secondary , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Antineoplastic Agents/administration & dosage , Humans , Ipilimumab , Lymphatic Metastasis , Male , Melanoma/diagnosis , Middle Aged , Treatment OutcomeSubject(s)
Catheterization, Peripheral , Certification/standards , Clinical Competence/standards , Competency-Based Education/standards , Education, Medical, Graduate/standards , Endovascular Procedures/education , Endovascular Procedures/standards , Peripheral Arterial Disease/therapy , Consensus , Germany , HumansABSTRACT
INTRODUCTION: A total of 17 cases of penetrating neck injury were managed by the otolaryngology team at King's College Hospital over a 3-year period in the 1980s. In April 2010 King's College Hospital became the major trauma centre for South East London. This prospective cohort study compares the incidence, changing demographic features and treatment outcomes of penetrating neck trauma in South East London over the previous 23 years. METHODS: Data were collected over a 12-month period (April 2010 to March 2011) and a selective management protocol was introduced to standardise initial investigations and further treatment. RESULTS: The past 23 years have seen a 550% increase in the incidence of penetrating neck injuries in South East London, with a marked increase in gun crime. Only 38% of cases underwent negative neck exploration in 2011 compared with 65% in 1987. Selective conservative management based on the absence of haemodynamic instability or radiological findings reduces length of hospital stay, lightens surgical workload and cuts costs without affecting morbidity or mortality. CONCLUSIONS: The increased incidence of penetrating neck injury is a reflection of more interpersonal violence rather than a consequence of the larger South East London trauma centre catchment area. Tackling this problem requires focus on wider issues of community prevention. Sharing of data between the four London trauma centres and the police is needed to help prevent interpersonal violence and develop a universal treatment algorithm for other institutions to follow.
Subject(s)
Neck Injuries/epidemiology , Wounds, Penetrating/epidemiology , Adult , Clinical Protocols , Female , Hematoma/etiology , Hematoma/therapy , Humans , Incidence , Injury Severity Score , Length of Stay , London/epidemiology , Male , Neck Injuries/therapy , Patient Care Team/statistics & numerical data , Prospective Studies , Trauma Centers/statistics & numerical data , Treatment Outcome , Wounds, Penetrating/therapyABSTRACT
A 35-year-old man presented with swelling, indurations and nodules on the thumb, wrist and fingers of the right hand. History revealed that the findings were slowly progressive and had been present for at least eight years. Histopathologic analysis of a nodule showed a diffuse infiltrate with atypical spindle-shaped cells and expression of cytokeratin, epithelial membrane antigen (EMA) and CD34; the diagnosis of epithelioid sarcoma (ES) was made. Because of diffuse extension of the tumor, forearm amputation was performed along with axillary dissection and local radiotherapy because of axillary lymph node metastases. ES is a rare subtype of soft tissue sarcoma with a harmless appearance and indolent course over years. ES represents a diagnostic challenge, with consequent delay in diagnosis and adequate treatment. The most important measure in the treatment of ES is early surgical excision with adjuvant radiotherapy if local metastases are present.
Subject(s)
Amputation, Surgical , Hand/pathology , Radiotherapy, Adjuvant , Sarcoma/pathology , Sarcoma/surgery , Adult , Humans , Male , Treatment OutcomeABSTRACT
Mitotane (o,p'-DDD), an oral adrenolytic agent for treatment of advanced adrenocortical carcinoma (ACC), is reported to inhibit cortisol biosynthesis in vitro and enhance production from exogenous cortisol of urinary 6ß-hydroxycortisol and unidentified polar unconjugated metabolites. We examined urinary steroid profiles by gas chromatography-mass spectrometry of patients with histologically confirmed ACC following surgery, receiving a) hydrocortisone alone (three males and three females) and b) mitotane and hydrocortisone (six males and 11 females). Samples were collected after plasma mitotane had reached the therapeutic range of 14-20âmg/l. Increased excretion of polar unconjugated steroids during mitotane treatment was confirmed, with 6ß-hydroxycortisol and 6ß-hydroxy-20-dihydrocortisols predominating. The proportion of additionally hydroxylated metabolites was <2% in untreated controls and 52, 35-52% (mean, range) in the mitotane plus hydrocortisone group. Ratios of 5α-/5ß- and 20ß-/20α-metabolites of administered cortisol were decreased 50-, 15-fold, and 14-, 8-fold respectively (males, females - mean values) but with no change in metabolite ratios that reflect oxidoreduction at C11 or C20. Patterns of decrease in 5α- relative to 5ß-reduced metabolites were similar to those of patients with 5α-reductase 2 deficiency or on treatment with the 5α-reductase 2 inhibitor finasteride but different from those of patients on dutasteride, indicating specific inhibition of 5α-reductase 2. We conclude that mitotane causes consistent changes in cortisol catabolism, most of which have not been previously recognised. These need not interfere with early detection of ACC recurrence. Induction of 6ß-hydroxylation offers an explanation for a reported decrease in cortisol bioavailability. Mitotane also has potential as a unique steroid metabolic probe for 20ß-reduction.
ABSTRACT
Khaya senegalensis (African mahogany or dry-zone mahogany) is a high-value hardwood timber species with great potential for forest plantations in northern Australia. The species is distributed across the sub-Saharan belt from Senegal to Sudan and Uganda. Because of heavy exploitation and constraints on natural regeneration and sustainable planting, it is now classified as a vulnerable species. Here, we describe the development of microsatellite markers for K. senegalensis using next-generation sequencing to assess its intra-specific diversity across its natural range, which is a key for successful breeding programs and effective conservation management of the species. Next-generation sequencing yielded 93,943 sequences with an average read length of 234 bp. The assembled sequences contained 1030 simple sequence repeats, with primers designed for 522 microsatellite loci. Twenty-one microsatellite loci were tested with 11 showing reliable amplification and polymorphism in K. senegalensis. The 11 novel microsatellites, together with one previously published, were used to assess 73 accessions belonging to the Australian K. senegalensis domestication program, sampled from across the natural range of the species. STRUCTURE analysis shows two major clusters, one comprising mainly accessions from west Africa (Senegal to Benin) and the second based in the far eastern limits of the range in Sudan and Uganda. Higher levels of genetic diversity were found in material from western Africa. This suggests that new seed collections from this region may yield more diverse genotypes than those originating from Sudan and Uganda in eastern Africa.
Subject(s)
Genetic Variation , Meliaceae/classification , Meliaceae/genetics , Microsatellite Repeats , Sequence Analysis, DNA/methods , Africa , Base Sequence , Genetic Markers , Molecular Sequence Data , Phylogeny , Polymorphism, Genetic , Species SpecificityABSTRACT
Pyoderma gangrenosum is a non-infectious neutro?philic skin disease commonly associated with underlying systemic diseases. Histopathological and laboratory diagnostics are unspecific in the majority of the cases and the diagnosis is made in accordance with the clinical picture. Here, we report the case of a 69-year old man with progredient pyoderma gangrenosum-like ulcerations under treatment with sunitinib due to hepatocellular carcinoma. A conventional ulcer therapy did not lead to a regression of the lesions. Solely cessation of sunitinib therapy resulted in an improvement of the ulcerations. Sunitinib is a multikinase inhibitor that targets the PDGF-α- and ?ß-, VEGF-1-3-, KIT-, FLT3-, CSF-1- and RET-receptor, thereby impairing tumour proliferation, pathological angiogenesis and metastasation. Here, we demonstrate that pyoderma gangrenosum-like ulcers may represent a serious side effect of sunitinib-based anti-cancer treatment.