Congenital generalized lipodystrophy: identification of novel variants and expansion of clinical spectrum.

Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder with two major subtypes. Variants in AGPAT2 result in CGL type 1 with milder manifestations, whereas BSCL2 variants cause CGL type 2 with more severe features. Muscle hypertrophy caused by lack of adipose tissue is present early in life in CGL patients. Our aim was to investigate 10 CGL patients from 7 different countries and report genotype-phenotype relationships. Genetic analysis identified disease-causing variants in AGPAT2 (five patients) and in BSCL2 (five patients), including three novel variants; c.134C>A (p.Ser45*), c.216C>G (p.Tyr72*) in AGPAT2 and c.458C>A (p.Ser153*) in BSCL2. We also report possible novel clinical features such as anemia, breast enlargement, steatorrhea, intraventricular hemorrhage and nephrolithiasis in CGL patients. Generalized lipodystrophy and muscular hypertrophy were the only features in all of our patients. Hepatomegaly was the second common feature. Some manifestations were exclusively noticed in our CGL2 patients; hypertrichosis, high-pitched voice and umbilical hernia. Bone cysts and history of seizures were noticed only in CGL1 patients. The findings of this study expand our knowledge of genotype-phenotype correlations in CGL patients. These results have important clinical applications in diagnosis and management of the CGL patients as well as in genetic counseling in families at-risk.

[Trauma bay haemoglobin level. Predictor of coagulation disorder in major trauma]. / Schockraumhämoglobin. Prädiktor für eine Gerinnungsstörung beim Traumapatienten.

BACKGROUND: Trauma-induced coagulopathy is common in patients with major trauma and requires early and appropriate treatment for bleeding control. Even in emergency laboratory, the availability of standard coagulation tests is associated with certain latencies and devices for viscoelastic haemostasis diagnosis (thromboelastometry) are not routinely established in major trauma centres. PURPOSE: We searched for a laboratory parameter with fast availability by point of care blood gas analysis and reliable correlation with coagulation parameters. METHODS: We analyzed the trauma patients of a single level one trauma centre from 2005-2011 and particularly evaluated the correlation between haemoglobin (Hb) and coagulation parameters and the correlation of Hb and parameters indicating tissue perfusion. All patients who were directly admitted from the scene of an accident to the trauma centre had an injury severity score (ISS) > 9, had a complete revised injury severity classification (RISC) and blood samples that were taken in the emergency department (ED) immediately after admission were included. Correlations were tested using the Pearson test (r) with a two-tailed significance level of p < 0.05. RESULTS: A total of 425 patients met inclusion criteria presenting with a mean age of 43 years, 76% male gender and mean ISS of 30.4. Significant correlation (p < 0.01) between Hb and prothrombin time (Quick) (r = 0.652), Hb and partial thromboplastin time (PTT) (r = - 0.434), Hb and platelet count (r = 0.501) and Hb and base excess (BE) (0.408) was found. No significant correlation between Hb and lactate was found. CONCLUSION: We found a robust correlation of Hb and Quick in a single centre trauma population. These data suggest that especially severely injured trauma patients with persistent bleeding might benefit from an Hb-based algorithm for early correction of coagulation disorders. Further studies with larger trauma populations are required to confirm our findings.

[Anesthesia in a patient after endoscopic lung volume reduction. First anesthesiological experiences with implanted endobronchial valves]. / Narkose bei einem Patienten mit Zustand nach endoskopischer Lungenvolumenreduktion. Erste anästhesiologische Erfahrungen mit implantierten "Lungenventilen"

Chronic obstructive pulmonary disease (COPD) is a disease with a high incidence and extensive comorbidities that make COPD a key challenge for anesthesiologists. A new treatment strategy, such as endoscopic lung volume reduction (ELVR) with implantation of endobronchial valves is a rapidly developing area which is still unknown to many anesthesiologists. This article therefore describes first experiences in a patient with five endobronchial valves in the right upper lobe who needed urgent surgery due to lumbar disc herniation with neurological impairment. After preoperative evaluation of the patient's condition, the use of bronchodilating volatile anesthetics and adjusting the ventilatory settings with long expiration times and low peak pressure in a pressure controlled mode seems favorable in these patients. Intraoperatively, the patient should be assessed with modern physiological monitoring tools to titrate the administration of anesthetic agents, opioids and myorelaxant drugs. In conclusion the care of patients with implanted endobronchial valves after ELVR does not differ from COPD patients without ELVR. A close cooperation between surgeons, anesthesiologists and internists is mandatory in the care of these patients.

Li-Fraumeni syndrome: multiple distinct brain tumours in two brothers.

Li-Fraumeni syndrome is a rare autosomal dominant cancer-prone condition characterized by the occurrence of a large set of different types of cancer in a patient and their family. A germline disease-causing mutation of the gene encoding the p53 protein is associated with the syndrome. We report on a family in which segregation of a TP53 mutation in two generations was associated with two brain tumours, a leiomyosarcoma and a thyroid carcinoma in four male patients. The main patient presented with seizures revealing several primary brain tumours. We review recent views on its molecular basis and discuss management of the condition as well as a review of the literature.

[Coagulation management of trauma patients with unstabile circulation : establishment of a hemoglobin-oriented standard operating procedure]. / Gerinnungsmanagement beim kreislaufinstabilen Polytraumapatienten : Erarbeitung einer hämoglobinorientierten "standard operating procedure"

INTRODUCTION: Massive hemorrhage is the leading cause of death in the first few hours following multiple trauma, therefore, early and aggressive treatment of clotting disorders and surgical intervention to stop the bleeding are of utmost importance. However, commonly performed clotting tests have a considerable latency of at least 30-45 min, whereas hemoglobin (Hb) levels can be tested very quickly. If a multiple trauma patient has already received fluid resuscitation, a certain relationship may be observed between the hemoglobin value and the development of clotting disturbances. Hence, hemoglobin may be a useful and rapidly available parameter for guiding the initial treatment of clotting disturbances in multiple trauma patients. METHODS: A Hb-guided algorithm has been developed to initiate initial clotting therapy. The algorithm contains three stages of different aggressive clotting therapy with fibrinogen, prothrombin complex concentrate (PCC), factor VIIa, tranexamic acid and desmopressin, depending on the first Hb value measured. For admission Hb levels > 5.5 mmol/l (≈8.8 g/dl) coagulation therapy is managed on the basis of the laboratory tests and if in doubt 2 g fibrinogen is administered. For admission Hb levels between 5.5 mmol/l (≈8.8 g/dl) and 4 mmol/l (≈6.5 g/dl) 2-4 g fibrinogen and 2,500-3,000 IU PCC are administered and tranexamic acid and desmopressin administration should be considered. For admission Hb levels < 4 mmol/l (≈6.5 g/dl) 4-6 g fibrinogen, 3,000-5,000 IU PCC and 1 mg factor VIIa should be administered and tranexamic acid and desmopression should be considered. All drugs mentioned should be stored in a special "coagulation box" in the hospital pharmacy and this box is brought immediately to the patient on demand. In addition to the use of clotting factors, infusions should be performed with balanced crystalloids and transfusions with an RBC/FFP ratio of 2:1-1:1. To assess the efficiency of the algorithm the routinely measured clotting parameters at trauma bay admission were compared with intensive care unit (ICU) admission and the standardized mortality ratio (SMR) was calculated. RESULTS: During a 6-month investigation period 71 severe multiple trauma patients were admitted to the trauma center and 19 patients were treated using the coagulation box of which 13 required massive transfusions. The routinely used clotting parameters markedly improved between admission to the trauma bay and ICU admission: Quick 61% versus 97% (p < 0.001), partial prothromboplastin time (PTT) 50 s versus 42 s (not significant), fibrinogen 1.7 g/l versus 2.15 g/l (not significant). Of the 19 patients 11 (58%) survived. The revised injury severity classification (RISC) predicted a survival rate of 40%, which corresponds to an SMR of 0.69, thus implying a higher survival rate than predicted. CONCLUSIONS: The Hb-driven algorithm, in combination with the coagulation box and the early use of clotting factors, may be a simple and effective tool for improving coagulopathy in multiple trauma patients.

[Methohexital for treatment of intracranial hypertension]. / Methohexital zur Therapie des erhöhten intrakraniellen Drucks.

BACKGROUND: Barbiturate coma therapy is a useful method to control increased intracranial pressure (ICP) in patients with severe brain damage if standard measures have failed to lower ICP. Pentobarbital (not available in Germany) and thiopental (in Germany only approved for induction of anesthesia) have frequently been used in patients with intracranial hypertension and the effects and side-effects are well-described. However, little is known about the effect of methohexital (the only barbiturate in Germany approved for maintaining anesthesia) in lowering increased ICP. Therefore, the effect of methohexital on ICP was studied in patients where standard measures had failed to control intracranial hypertension. METHOD: A retrospective observational study was carried out with the inclusion criteria of patient age ≥18 years and methohexital therapy for 12 h or more with ICP monitoring in place. Methohexital was administered following a standardized algorithm to patients for whom standard measures, such as deep anesthesia, normoventilation, cerebral perfusion pressure (CPP) >65 mmHg, osmotherapy, neurosurgical evacuation of mass lesions, had failed to lower ICP. Methohexital was used if the ICP had risen above 20-25 mmHg for more the 20-30 min and otherwise manageable causes for the ICP increase had been ruled out. Methohexital was given continuously in addition to standard analgesia and sedation in doses of 2-4-6 mg/kg body weight (BW), depending on the ICP lowering effect. The records of the patient data management system from the years 2008/2009 were used to compare the ICP and CPP before and during methohexital administration. For statistical analyses Student's t-test was applied for measured values and the χ(2)-test was applied for percentage values whereby p<0.05 was defined as being statistically significant. RESULTS: During the study period 36 patients required methohexital therapy and 30 fulfilled the inclusion criteria. In 26 out of 30 patients the data were complete and these 26 patients were included in the data analyses. Of the patients 6 (23%) died due to elevated intracranial hypertension and 20 patients (77%) survived. In all patients methohexital lowered the ICP from 25.2 mmHg (standard deviation, SD ±4.3 mmHg) to 19.8 mmHg (SD ±12.5 mmHg) within the first 24 h, this result closely failed to reach a level of significance. In the 20 survivors methohexital lowered the ICP from 25.88 mmHg (SD ±4.8 mmHg) to 14.25 mmHg (SD ±6.9 mmHg) within the first 24 h, which is statistically highly significant. In non-survivors the ICP had risen from 24 mmHg (SD ±2.6 mmHg) to 32 mmHg (SD ±16.3 mmHg) within the first 24 h despite all efforts. Due to the CPP driven volume and vasopressor therapy no significant changes in the CPP during methohexital administration were observed. No significant changes in brain temperature (as possible cause for the decrease of the ICP) were observed. Non-survivors received significantly more methohexital due to increased ICP and required significantly more vasopressor therapy to maintain a sufficient CPP. CONCLUSIONS: Methohexital showed a clear trend for decreasing ICP in patients with intracranial hypertension refractory to standard therapeutic measures. In survivors the effect was highly significant. Patients not responding to methohexital therapy seemed to have an unfavorable outcome.

[Different case fatality rates at German trauma centres : Critical analysis]. / Unterschiedliche Letalitätsraten an deutschen Traumazentren : Kritische Analyse.

OBJECTIVE: The level of trauma care in Germany belongs to one of the best worldwide. Nevertheless, previous studies have shown significant differences in the case fatality rates of multiple trauma patients in German trauma centres. The objective of this study was to indentify the reasons for the different outcomes based on data of the trauma registry of the German Society of Orthopaedic Surgery and Traumatology. METHODS: Due to the inadequacy of comparing only the case fataltiy rates in the different trauma centres, the data recorded in the trauma registry were analyzed in a retrospective, multicentre study to calculate the probability of survival, revised injury severity classification (RISC) and, additionally, the standardized mortality ratio (SMR) for ranking of the participating trauma centres. As a criterion for inclusion in the study, a minimum of 100 trauma patients admitted directly from the scene within a 4 year period was set. The ranking was carried out using the SMR (observed mortality divided by probability of survival). With the help of data from the trauma registry an attempt was made to find the differences in trauma management between the top 10 centres (lowest SMR), the 10 middle and the last 10 centres (highest SMR) in the ranking. RESULTS: The data of 6,522 patients were included in the study. There were significant differences in the pre-hospital time, the time spent in the emergency room (ER) and time until a CT scan had been performed. Pre-hospital time was longer in patients admitted to the top centres, whereas time in the ER was longer in the last centres of the ranking. Comparing the sum of pre-hospital time and time in the ER, there were no differences between the top and the last centres. At the scene of accident overall intubation rate and intubation rate in patients with traumatic brain injury were higher in patients admitted to the top centres. Regarding the transport modality, significantly more patients were transported by helicopter in the group of the top centres. In top centres CT scans, in particular whole-body CTs, were initiated sooner and used much more frequently so that the rate of missed injuries was much lower. The amount of fluid given at the scene of accident did not differ between the centres but the amount of fluid given in ER and the operating room until admission to the intensive care unit was significantly higher in the top centres. CONCLUSION: There are significant differences in the pre-hospital and clinical care of patients admitted to German trauma centres. Under clinical conditions a tight time management, an immediate and complete diagnostic approach, particularly by means of whole-body CT and a liberal fluid resuscitation seem to be favorable factors.

[Desmopressin (Minirin) in multiple trauma--a case report]. / Desmopressin (Minirin) beim schweren Trauma--eine Fallbeschreibung.

Bleeding and clotting disturbances are not uncommon in trauma patients and require an early and consequent therapy. Under the prevalent pathophysiological circumstances of hypothermia, acidosis and clotting disturbances, desmopressin seems to be a possible option to control diffuse bleeding. We report about 2 trauma patients with diffuse bleeding and in whom desmopressin was used successfully to control bleeding from the point of view of the authors. We discuss the advantages and disadvantages of desmopressin in the 2 patients.

Severe cardiac phenotype of Berardinelli-Seip congenital lipodystrophy in an infant with homozygous E189X BSCL2 mutation.

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare autosomal recessive condition associating insulin resistance, absence of subcutaneous fat and muscular hypertrophy. Disease-causing mutations have been described in AGPAT2 and BSCL2 genes. Hypertrophic cardiomyopathy is a classical late (third decade) complication which has only been occasionally described in childhood. We report on a 4-month-old Chinese male infant who presented with a severe BSCL "cardiac" phenotype comprising heart failure, hypertension and hypertrophic cardiomyopathy.

Congenital generalized lipodystrophy in an Indian patient with a novel mutation in BSCL2 gene.

Congenital generalized lipodystrophy (CGL) is an autosomal recessive metabolic syndrome with involvement of multiple organs. Mutations in BSCL2 are known to be associated with a severe form of CGL and mental retardation (MR). The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity in different ethnic groups. Studies in the Indian context are very few in this regard. We report here a detailed clinical analysis of a CGL case from infancy to adult hood. Interestingly, the patient was found to be homozygous for a novel BSCL2 mutation, but with normal intellectual development contrasting with the MR associated with BSCL2 mutation in CGL patients. The biochemical investigations at the time of diagnosis (9 months) included total cholesterol, total lipids, triglycerides, phospholipids, ß-lipoprotein and free fatty acids, which were above normal limits. The clinical phenotype, viz. lack of subcutaneous fat, hepatosplenomegaly, cardiomegaly, and advanced bone age was also documented. The patient was found to be insulin resistant and diabetes mellitus was diagnosed by age 13 years. Ultrasonography of the ovaries at age 22 showed polycystic features with elevated levels of gonadotropins and negligible levels of serum leptin. For genetic analysis, direct DNA sequencing of BSCL2 was carried out and disclosed an 11-base-pair deletion in exon 6 (H217fsX272) resulting in a truncated protein. This is a novel mutation that contributes to CGL formation in a family of Indian origin and adds to the array of variants reported in this disorder. Moreover, the novel mutation is found to be associated with normal intellectual ability.

[Misleading anisocoria in a comatose 15-year-old with head injury]. / Irreführende Anisokorie bei komatöser 15-Jähriger mit Kopfverletzung.

Anisocoria after blunt head trauma, associated with altered vigilance, is not unusually assumed to expanding intracranial mass lesion. Obvious signs of head-trauma and vomiting might strengthen this diagnosis. We report from an unconscious 15-year-old girl (Glasgow-Coma-Scale score 3) that showed these symptoms secondary after head-trauma due to alcohol intoxication but turned out to be misleading after cranial computed tomography (CT). Surprisingly, an artificial eye was found that previously remained undetected in clinical examination. Artificial eyes implemented after enucleation therapy in retinoblastoma or eye-trauma are nowadays perfectly fitting. Prehospital discrimination of artificial eyes and natural eyes might be difficult in comatose emergency patients. Neurological examination should check corneal reflex and manual palpation of the bulbus. Independent from anisocoria, patients presenting GCS 3 and head injury need rapid admission to CT-diagnostic, neurosurgical treatment respectively.

[Prevention of thromboembolism in German intensive care units : Results of a nationwide survey]. / Thrombembolieprophylaxe auf deutschen Intensivstationen : Ergebnisse einer bundesweiten Umfrage.

BACKGROUND: Intensive care unit (ICU) patients have a high risk of developing venous thromboembolism (VTE) and prophylaxis is recommended. Venous thromboembolism confers considerable morbidity and mortality in hospitalized patients, although few studies have focused on critically ill patients. METHOD AND OBJECTIVE: A systematic prospective mailed self-administered survey of 645 German ICU directors was performed, representing 652 ICUs throughout the country. The objective of this study was to understand current approaches to the prevention of VTE among patients in ICUs. RESULTS: Of the 652 ICUs approached, 470 (72.3%) participated. Thromboembolism prophylaxis was prescribed in 98% of the ICUs. For mechanical prophylaxis graded elastic stockings were used in 93% and pneumatic compression devices in 24%. For pharmacologic prophylaxis low molecular weight heparin was the predominant prophylactic strategy in 88%, whereas unfractionated heparin was used less often in 45%. CONCLUSION: The prescribed prophylaxis for thromboembolism in 98% of the German ICUs is surprisingly high compared to that given in the literature. A combination of mechanical and pharmacologic prophylaxis is the predominant prophylactic strategy.

Recommendations for locus-specific databases and their curation.

Expert curation and complete collection of mutations in genes that affect human health is essential for proper genetic healthcare and research. Expert curation is given by the curators of gene-specific mutation databases or locus-specific databases (LSDBs). While there are over 700 such databases, they vary in their content, completeness, time available for curation, and the expertise of the curator. Curation and LSDBs have been discussed, written about, and protocols have been provided for over 10 years, but there have been no formal recommendations for the ideal form of these entities. This work initiates a discussion on this topic to assist future efforts in human genetics. Further discussion is welcome.

A structured simple form for ordering genetic tests is needed to ensure coupling of clinical detail (phenotype) with DNA variants (genotype) to ensure utility in publication and databases.

Researchers and clinicians ideally need instant access to all the variation in their gene/locus of interest to efficiently conduct their research and genetic healthcare to the highest standards. Currently much key data resides in the laboratory books or patient records around the world, as there are many impediments to submitting this data. It would be ideal therefore if a semiautomated pathway was available, with a minimum of effort, to make the deidentified data publicly available for others to use. The Human Variome Project (HVP) meeting listed 96 recommendations to work toward this situation. This article is planned to initiate a strategy to enhance the collection of phenotype and genotype data from the clinician/diagnostic laboratory nexus. Thus, the aim is to develop universally applicable forms that people can use when investigating patients for each inherited disease, to assist in satisfying many of the recommendations of the HVP Meeting [Cotton et al., 2007]. We call for comment and collaboration in this article.

New aspects in the emergency room management of critically injured patients: a multi-slice CT-oriented care algorithm.

BACKGROUND: Time-critical care of seriously injured patients is gaining more and more significance. The availability of the multi-slice CT allows a complete diagnostic assessment of injured patients in 90-240 s, but is presently carried out only at the conclusion of basic diagnostics. We investigated the effects of a clinical algorithm using multi-slice CT scanning ahead of other measures in the clinical care of seriously injured patients. METHODS: Availability of a trauma admitting room with integrated multi-slice CT scanner enabled a new algorithm for patient care. We prospectively examined the time taken to reach established benchmarks in clinical care (completion of diagnosis, completion of resuscitation, exit from the trauma room) under this new approach. Data were collected for consecutive patients with serious injury (estimated injury severity score >15), and compared to historical data from the previous 2 years. RESULTS: The new algorithm was employed in 139 patients with a mean ISS of 26.93. CT scanning was initiated 8 min (S.D. 5.7) after patient arrival, and concluded 13 min (S.D. 8.4) after patient arrival. Stabilising measures (initial resuscitation) were completed an average of 36 min from patient arrival. The length of stay in the trauma room was reduced to an average of 38 min (S.D. 19.1). Four patients required life-saving interventions after admission to the trauma room but before CT scanning began. CONCLUSIONS: A new algorithm for trauma patient care that integrates high resolution CT scanning into the early diagnostic protocol reduces the length of stay in the trauma room markedly, and will facilitate rapid therapeutic intervention in patients with unstable haemorrhagic shock or neurosurgical emergencies.

[Arterial air embolism following multiple injuries after a fall from the tenth floor]. / Arterielle Luftembolie nach Polytraumatisierung bei Sturz aus dem 10. Stock.

We report about the case of a 20-year-old patient who fell from the tenth floor. The patient suffered multiple injuries and systemic gas embolism. He survived his injuries despite CPR, massive transfusion, development of ARDS and SIRS with minimal neurological deficit. The possible pathogenesis of the systemic gas embolism as well as the therapy are discussed. Besides stabilizing the circulation with i.v. fluids, blood transfusion and catecholamine therapy, the use of hyperbaric oxygenation was the decisive therapeutic measure.

Clinical findings and PDS mutations in 15 patients with hearing loss and dilatation of the vestibular aqueduct.

Following systematic skull imaging of hundred and sixty seven individuals attending a medical referral centre for the deaf in Brussels, Belgium, fifteen patients (9 per cent) aged between two and 25 years were diagnosed with dilatation of the vestibular aqueduct. Careful audiological study, with a baseline assessment then longitudinal follow up, indicated mild to profound deafness with a progressive course (i.e. an average loss of 3.3 dB per year) and frequent dizziness. Sequencing of PDS was performed in all individuals. Alterations of this gene (either homozygous, heterozygous or compound heterozygous base changes) were found in 53 per cent of patients with a large vestibular aqueduct. Four new mutations (two missense, a splice site and a four base pair insertion) were described. We were unable to confirm a correlation between homozygosity, heterozygosity and a Pendred or deafness-only phenotype.