Emergencies in obstetric anaesthesia: a narrative review.

We conducted a narrative review in six areas of obstetric emergencies: category-1 caesarean section; difficult and failed airway; massive obstetric haemorrhage; hypertensive crisis; emergencies related to neuraxial anaesthesia; and maternal cardiac arrest. These areas represent significant research published within the last five years, with emphasis on large multicentre randomised trials, national or international practice guidelines and recommendations from major professional societies. Key topics discussed: prevention and management of failed neuraxial technique; role of high-flow nasal oxygenation and choice of neuromuscular drug in obstetric patients; prevention of accidental awareness during general anaesthesia; management of the difficult and failed obstetric airway; current perspectives on the use of tranexamic acid, fibrinogen concentrate and cell salvage; guidance on neuraxial placement in a thrombocytopenic obstetric patient; management of neuraxial drug errors, local anaesthetic systemic toxicity and unusually prolonged neuraxial block regression; and extracorporeal membrane oxygenation use in maternal cardiac arrest.

All-atom molecular dynamics simulations of spin labelled double and single-strand DNA for EPR studies.

We report the first application of fully atomistic molecular dynamics (MD) simulations to the prediction of electron paramagnetic resonance (EPR) spectra of spin labelled DNA. Models for two structurally different DNA spin probes with either the rigid or flexible position of the nitroxide group in the base pair, employed in experimental studies previously, have been developed. By the application of the combined MD-EPR simulation methodology we aimed at the following. Firstly, to provide a test bed against a sensitive spectroscopic technique for the recently developed improved version of the parmbsc1 force field for MD modelling of DNA. The predicted EPR spectra show good agreement with the experimental ones available from the literature, thus confirming the accuracy of the currently employed DNA force fields. Secondly, to provide a quantitative interpretation of the motional contributions into the dynamics of spin probes in both duplex and single-strand DNA fragments and to analyse their perturbing effects on the local DNA structure. Finally, a combination of MD and EPR allowed us to test the validity of the application of the Model-Free (M-F) approach coupled with the partial averaging of magnetic tensors to the simulation of EPR spectra of DNA systems by comparing the resultant EPR spectra with those simulated directly from MD trajectories. The advantage of the M-F based EPR simulation approach over the direct propagation techniques is that it requires motional and order parameters that can be calculated from shorter MD trajectories. The reported MD-EPR methodology is transferable to the prediction and interpretation of EPR spectra of higher order DNA structures with novel types of spin labels.

Mutational spectrum of Duchenne muscular dystrophy in Spain: Study of 284 cases. / Espectro mutacional de la distrofia muscular de Duchenne en España: estudio de 284 casos.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disease that affects one in 3500 live-born males. The total absence of dystrophin observed in DMD patients is generally caused by mutations that disrupt the reading frame of the DMD gene, and about 80% of cases harbour deletions or duplications of one or more exons. METHODS: We reviewed 284 cases of males with a genetic diagnosis of DMD between 2007 and 2014. These patients were selected from 8 Spanish reference hospitals representing most areas of Spain. Multiplex PCR, MLPA, and sequencing were performed to identify mutations. RESULTS: Most of these DMD patients present large deletions (46.1%) or large duplications (19.7%) in the dystrophin gene. The remaining 34.2% correspond to point mutations, and half of these correspond to nonsense mutations. In this study we identified 23 new mutations in DMD: 7 large deletions and 16 point mutations. CONCLUSIONS: The algorithm for genetic diagnosis applied by the participating centres is the most appropriate for genotyping patients with DMD. The genetic specificity of different therapies currently being developed emphasises the importance of identifying the mutation appearing in each patient; 38.7% of the cases in this series are eligible to participate in current clinical trials.

Three new HLA class II alleles: DRB1*08:70, DQA1*01:13 and DQA1*03:01:03.

Three novel HLA class II alleles, DRB1*08:70, DQA1*01:13 and DQA1*03:01:03, were characterized.

Efficacy of antimicrobial and nutraceutical treatment for canine acute diarrhoea: A systematic review and meta-analysis for European Network for Optimization of Antimicrobial Therapy (ENOVAT) guidelines.

Systemic antimicrobial treatments are commonly prescribed to dogs with acute diarrhoea, while nutraceuticals (prebiotics, probiotics, and synbiotics) are frequently administered as an alternative treatment. The aim of this systematic review and meta-analysis was to assess the effectiveness of antimicrobials and nutraceutical preparations for treatment of canine acute diarrhoea (CAD). The results of this study will be used to create evidence-based treatment guidelines. PICOs (population, intervention, comparator, and outcome) were generated by a multidisciplinary expert panel taking into account opinions from stakeholders (general practitioners and dog owners). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to evaluate the certainty of the evidence. The systematic search yielded six randomised controlled trials (RCT) for antimicrobial treatment and six RCTs for nutraceutical treatment meeting the eligibility criteria. Categories of disease severity (mild, moderate, and severe) were created based on the presence of systemic signs and response to fluid therapy. Outcomes included duration of diarrhoea, duration of hospitalization, progression of disease, mortality, and adverse effects. High certainty evidence showed that antimicrobial treatment did not have a clinically relevant effect on any outcome in dogs with mild or moderate disease. Certainty of evidence was low for dogs with severe disease. Nutraceutical products did not show a clinically significant effect in shortening the duration of diarrhoea (based on very low to moderate certainty evidence). No adverse effects were reported in any of the studies.

European Network for Optimization of Veterinary Antimicrobial Therapy (ENOVAT) guidelines for antimicrobial use in canine acute diarrhoea.

Acute diarrhoea is a common presentation in dogs, and a common reason for antimicrobial prescription and nutraceutical use. This evidence-based guideline provides recommendations for antimicrobial and probiotic treatment of canine acute diarrhoea (CAD). A multidisciplinary panel developed the recommendations by adhering to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. The opinions of stakeholders (general veterinary practitioners and dog owners) were collected and incorporated to ensure the applicability of this guideline. Four strong recommendations informed by high certainty evidence, and three conditional recommendations informed by very low or low certainty evidence, were drafted by the panel, along with an ungraded section on diagnostic work-up of dogs with acute diarrhoea. The ENOVAT guidelines initiative encourages national or regional guideline makers to use the evidence presented in this document, and the supporting systematic review, to draft national or local guidance documents.

Diagnostic findings in sinonasal aspergillosis in dogs in the United Kingdom: 475 cases (2011-2021).

OBJECTIVES: To describe the diagnostic tests used and their comparative performance in dogs diagnosed with sinonasal aspergillosis in the United Kingdom. A secondary objective was to describe the signalment, clinical findings and common clinicopathologic abnormalities in sinonasal aspergillosis. MATERIALS AND METHODS: A multi-centre retrospective survey was performed involving 23 referral centres in the United Kingdom to identify dogs diagnosed with sinonasal aspergillosis from January 2011 to December 2021. Dogs were included if fungal plaques were seen during rhinoscopy or if ancillary testing (via histopathology, culture, cytology, serology or PCR) was positive and other differential diagnoses were excluded. RESULTS: A total of 662 cases were entered into the database across the 23 referral centres. Four hundred and seventy-five cases met the study inclusion criteria. Of these, 419 dogs had fungal plaques and compatible clinical signs. Fungal plaques were not seen in 56 dogs with turbinate destruction that had compatible clinical signs and a positive ancillary test result. Ancillary diagnostics were performed in 312 of 419 (74%) dogs with observed fungal plaques permitting calculation of sensitivity of cytology as 67%, fungal culture 59%, histopathology 47% and PCR 71%. CLINICAL SIGNIFICANCE: The sensitivities of ancillary diagnostics in this study were lower than previously reported challenging the clinical utility of such tests in sinonasal aspergillosis. Treatment and management decisions should be based on a combination of diagnostics including imaging findings, visual inspection, and ancillary testing, rather than ancillary tests alone.

Menstrual psychosis.

In this report, we explore a case of symptoms consistent with menstrual psychosis. In order to do this, a review of the literature relating to this topic was conducted and a report was written. This is a case of a previously well adolescent female who experienced psychotic symptoms in the pre-menstrual phase of her cycle and became well soon after her menstrual period began. These episodes were prevented by aripiprazole, but recurred once medication was withdrawn. We conclude that psychosis in some women may have a relationship with the menstrual cycle. In women presenting with psychosis, it may be appropriate to note menstrual variation in symptoms. This could have a potential role in individualisation of treatment for women with psychotic disorders.

Prevalence of methicillin resistance in Staphylococcus pseudintermedius isolates from dogs with skin and ear infections in South Africa.

ABSTRACT: Staphylococcus pseudintermedius (SP) is an important opportunistic pathogen, frequently associated with pyoderma and otitis in dogs. The emergence and rapid expansion of methicillin-resistant Staphylococcus pseudintermedius (MRSP) is problematic due to multidrug resistance and reduced treatment options. The aim of this study was to determine i) the prevalence of MRSP in dogs with pyoderma or otitis externa, ii) the antimicrobial resistance patterns of MRSP from South African isolates, and iii) the risk factors for MRSP-associated pyoderma or otitis externa in dogs in South Africa (RSA). Sixty-eight presumptive clinical SP isolates (collected from 65 dogs) from five geographically dispersed laboratories in RSA were collected over 2 years. Possible MRSP isolates were flagged when resistance to oxacillin was observed. Thereafter, all isolates were confirmed as SP by polymerase chain reaction (PCR) and further genotyped for the mecA gene. Fifty-seven of 68 isolates were confirmed to be SP (83.8%), while 49/57 (85.9%) carried mecA. Our findings showed that preliminary phenotypic methods supplemented by genotypic methods increased the accuracy of correctly identifying SP. All isolates were resistant to at least one antimicrobial drug. There was a high incidence of amoxicillin (70.1%) and enrofloxacin (65%) resistance. Important risk factors for mecA positive carriage were previous hospital admission, pruritus, and previous antibacterial failure. This study demonstrates a high prevalence of mecA positive carriage (85.9% of samples) in MRSP pyoderma and otitis in dogs in RSA. There is an urgent need for better laboratory diagnosis of MRSP and surveillance of dogs presenting with pyoderma and otitis in South Africa.

The role of cannabinoids in neurodevelopmental disorders of children and adolescents. / El papel de los cannabinoides en los trastornos del neurodesarrollo de niños y adolescentes.

INTRODUCTION: Neurodevelopmental disorders have a multifactorial etiology that results from the interaction between biological and environmental factors. The biological basis of many of these disorders is only partially understood, which makes therapeutic interventions, especially pharmacological ones, particularly difficult. The impact of medical cannabis on neurological and psychiatric disorders has been studied for a long time. This study aimed to review the currently available clinical and pre-clinical studies regarding the use of cannabinoids in pediatric neurodevelopmental disorders and to draw attention to the potential therapeutic role of cannabidiol in this field. DEVELOPMENT: Cannabidiol is an endocannabinoid system modulator and exerts its effects on both developing and mature brains through numerous mechanisms. Cannabidiol holds a relatively high toxicity limit and current literature suggests that it may have anxiolytic, antipsychotic, and neuroprotective properties. Clinical evidence suggests that early treatment with cannabidiol might be a promising therapy for neurodevelopmental disorders, including intellectual disability, autism spectrum disorders, tics, and attention/deficit hyperactivity disorder. CONCLUSIONS: This review hopefully draws attention to an emerging body of evidence concerning cannabidiol's significant potential to safely improve many of the common symptoms affecting children and adolescents with neurodevelopmental disorders, especially autism spectrum disorder.

TITLE: El papel de los cannabinoides en los trastornos del neurodesarrollo de niños y adolescentes.Introducción. Los trastornos del neurodesarrollo tienen una etiología multifactorial que resulta de la interacción entre factores biológicos y ambientales. La base biológica de muchos de estos trastornos se comprende sólo parcialmente, lo que hace que las intervenciones terapéuticas, especialmente las farmacológicas, sean particularmente difíciles. El impacto del cannabis medicinal en los trastornos neurológicos y psiquiátricos se ha estudiado durante mucho tiempo. Este estudio tuvo como objetivo revisar los estudios clínicos y preclínicos actualmente disponibles con respecto al uso de cannabinoides en trastornos del neurodesarrollo pediátrico y llamar la atención sobre el posible papel terapéutico del cannabidiol en este campo. Desarrollo. El cannabidiol es un modulador del sistema endocannabinoide y ejerce sus efectos tanto en cerebros en desarrollo como en cerebros maduros a través de numerosos mecanismos. El cannabidiol tiene un límite de toxicidad relativamente alto, y la bibliografía actual sugiere que puede tener propiedades ansiolíticas, antipsicóticas y neuroprotectoras. La evidencia clínica sugiere que el tratamiento temprano con cannabidiol podría ser una terapia prometedora para los trastornos del desarrollo neurológico, incluida la discapacidad intelectual, los trastornos del espectro autista, los tics y el trastorno por déficit de atención/hiperactividad. Conclusiones. Es de esperar que esta revisión llame la atención sobre un cuerpo emergente de evidencia sobre el potencial significativo del cannabidiol para mejorar de manera segura muchos de los síntomas comunes que afectan a niños y adolescentes con trastornos del neurodesarrollo, especialmente el trastorno del espectro autista.

Phase II study of sunitinib as first-line treatment of urothelial cancer patients ineligible to receive cisplatin-based chemotherapy: baseline interleukin-8 and tumor contrast enhancement as potential predictive factors of activity.

BACKGROUND: A strong rationale supports the role of antiangiogenic drugs in urothelial cancer. This trial was designed to assess the activity of sunitinib as first-line treatment in patients with metastatic urothelial cancer ineligible for cisplatin and to explore molecular and imaging variables predictive of clinical benefit. PATIENTS AND METHODS: This was a multicenter phase II trial with sunitinib 50 mg daily in 4/2-week schedule. Eligibility criteria were as follows: creatinine clearance 30-60 ml/min, Eastern Cooperative Oncology Group Pperformance Sstatus of one or less, and adequate hepatic and hematologic function. Twelve circulating cytokines were evaluated at baseline and sequentially using Luminex xMAP(®) (Austin, TX). Baseline and treatment-related changes in perfusion were evaluated in a patient subgroup using contrast-enhanced computed tomography. RESULTS: On intention-to-treat analysis, 38 patients showed 3 (8%) partial responses (PRs) and 19 (50%) presented with stable disease (SD), 17 (45%) of them ≥3 months. Clinical benefit (PR + SD) was 58%. Median time to progression (TTP) was 4.8 months and median overall survival 8.1 months. Toxicity was consistent with previous reports for sunitinib. Low interleukin-8 (IL-8) baseline levels were significantly associated with increased TTP. Baseline tumor contrast enhancement with >40 Hounsfield units was associated with clinical benefit. CONCLUSIONS: This study highlights the potential role of the angiogenic pathway as a therapy target in urothelial cancer. Baseline IL-8 serum levels and contrast enhancement of lesions warrant further study.

Direct evidence that twisted flux tube emergence creates solar active regions.

The magnetic nature of the formation of solar active regions lies at the heart of understanding solar activity and, in particular, solar eruptions. A widespread model, used in many theoretical studies, simulations and the interpretation of observations, is that the basic structure of an active region is created by the emergence of a large tube of pre-twisted magnetic field. Despite plausible reasons and the availability of various proxies suggesting the accuracy of this model, there has not yet been a methodology that can clearly and directly identify the emergence of large pre-twisted magnetic flux tubes. Here, we present a clear signature of the emergence of pre-twisted magnetic flux tubes by investigating a robust topological quantity, called magnetic winding, in solar observations. This quantity detects the emerging magnetic topology despite the significant deformation experienced by the emerging magnetic field. Magnetic winding complements existing measures, such as magnetic helicity, by providing distinct information about field line topology, thus allowing for the direct identification of emerging twisted magnetic flux tubes.

Peripartum management of a parturient with type 1C (clearance) von Willebrand disease.

Peripartum replacement of factor VIII and von Willebrand factor is not usually required in type 1 von Willebrand disease, as the levels of endogenous factors tend to increase to within the normal range as a physiological change of pregnancy. However, there is wide heterogeneity of genotypes and phenotypes associated with type 1 von Willebrand disease. Here, we describe the anesthetic management of a parturient with type 1C von Willebrand disease, a subtype characterized by decreased plasma von Willebrand factor survival.

[Statement of the Austrian Society of Pneumology (ASP)]. / Stellungnahme der Österreichischen Gesellschaft für Pneumologie (ÖGP): Management von Patienten mit SARS-CoV-2-Infektionen und von Patienten mit chronischen Lungenerkrankungen während der COVID-19-Pandemie (Stand 27.04.2020).

The COVID-19 pandemic is currently a challenge worldwide. In Austria, a crisis within the health care system has so far been avoided. The treatment of patients with community-acquired pneumonia (CAP), including SARS-CoV­2 infections, should continue to be based on evidence-based CAP guidelines during the pandemic. However, COVID-19-specific adjustments are useful. The treatment of patients with chronic lung diseases must be adapted during the pandemic, but must still be guaranteed.

Identification of TNF-alpha and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array.

BACKGROUND: Several drugs are available to treat metastatic renal-cell carcinoma (MRCC), and predictive markers to identify the most adequate treatment for each patient are needed. Our objective was to identify potential predictive markers of sunitinib activity in MRCC. METHODS: We collected sequential serum samples from 31 patients treated with sunitinib. Sera of six patients with extreme phenotypes of either marked responses or clear progressions were analysed with a Human Cytokine Array which evaluates 174 cytokines before and after treatment. Variations in cytokine signal intensity were compared between both groups and the most relevant cytokines were assessed by ELISA in all the patients. RESULTS: Twenty-seven of the 174 cytokines varied significantly between both groups. Five of them (TNF-alpha, MMP-9, ICAM-1, BDNF and SDF-1) were assessed by ELISA in 21 evaluable patients. TNF-alpha and MMP-9 baseline levels were significantly increased in non-responders and significantly associated with reduced overall survival and time-to-progression, respectively. The area under the ROC curves for TNF-alpha and MMP-9 as predictive markers of sunitinib activity were 0.83 and 0.77. CONCLUSION: Baseline levels of TNF-alpha and MMP-9 warrant further study as predictive markers of sunitinib activity in MRCC. Selection of patients with extreme phenotypes seems a valid method to identify potential predictive factors of response.

The hexokinase gene is required for transcriptional regulation of the glucose transporter gene RAG1 in Kluyveromyces lactis.

The RAG1 gene of Kluyveromyces lactis encodes a low-affinity glucose/fructose transporter. Its transcription is induced by glucose, fructose, and several other sugars. The RAG4, RAG5, and RAG8 genes are trans-acting genes controlling the expression of the RAG1 gene. We report here the characterization of one of these genes, RAG5. The nucleotide sequence of the cloned RAG5 gene indicated that it encodes a protein that is homologous to hexokinases of Saccharomyces cerevisiae. rag5 mutants showed no detectable hexokinase or glucokinase activity, suggesting that the sugar kinase activity encoded by this gene is the only hexokinase in K. lactis. Both high- and low-affinity transport systems of glucose were affected in rag5 mutants. The defect of the low-affinity component was found to be due to a block of transcription of the RAG1 gene by the hexokinase mutation. In vivo complementation of the rag5 mutation by the HXK2 gene of S. cerevisiae and complementation of hxk1 hxk2 mutations of S. cerevisiae by the RAG5 gene showed that RAG5 and HXK2 were equivalent for sugar-phosphorylating activity but that RAG5 could not restore glucose repression in the S. cerevisiae hexokinase mutants.

Hypoxanthine effect on equilibrative and concentrative adenosine transport in human lymphocytes: implications in the phatogenesis of Lesch-Nyhan syndrome.

We postulated that increased levels of hypoxanthine, a main characteristic of hypoxanthine phosphoribosyltransferase (HPRT) deficiency, may influence adenosine function which could be related to some of the neurological features of the Lesch-Nyhan syndrome. We have examined the effect of hypoxanthine on different adenosine transporters in peripheral blood lymphocytes from control subjects. Increased hypoxanthine concentrations (25 microM) significantly decreased adenosine transport. The equilibrative adenosine transporters (79.6% of the adenosine transport), both NBTI sensitive and NBTI insensitive, were affected significantly. In contrast, the concentrative adenosine transporters were not influenced by hypoxanthine. These results supports the hypothesis that increased hypoxanthine levels influence equilibrative (predominantly NBTI-insensitive type) adenosine transporters.

Efficacy and safety of allopurinol in patients with the Lesch-Nyhan syndrome and partial hypoxanthine- phosphoribosyltransferase deficiency: a follow-up study of 18 Spanish patients.

Allopurinol is used widely for the treatment of purine disorders such as gout, but efficacy and safety of allopurinol has not been analyzed systematically in an extensive series of patients with HPRT deficiency. From 1984 to 2004 we have diagnosed 30 patients with HPRT deficiency. Eighteen patients (12 with Lesch-Nyhan syndrome or complete HPRT deficiency, and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.44 mg/Kg of weight per day) and followed-up for at least 12 months (mean follow-up 7,6 years per patient). Mean age at diagnosis was 7 years (range, 5 months to 35 years). Treatment with allopurinol was associated to a mean reduction of serum urate concentration of 50%, and was normalized in all patients. Mean urinary uric acid excretion was reduced by 75% from baseline values, and uric acid to creatinine ratio was close or under 1.0 in all patients. In contrast, hypoxanthine and xanthine urinary excretion rates increased by a mean of 6 and 10 times, respectively, compared to baseline levels. These modifications were similar in patients with complete or partial HPRT deficiency. In 2 patients xanthine stones were documented despite allopurinol dose adjustments to prevent markedly increased oxypurine excretion rates. Neurological manifestations did not appear to be influenced by allopurinol therapy. Allopurinol is a very efficacy and fairly safety drug for the treatment of uric acid overproduction in patients with complete and partial HPRT deficiency. Allopurinol was associated with xanthine lithiasis.

Familial nephropathy associated with hyperuricemia in Spain: our experience with 3 families harbouring a UMOD mutation.

Since 1993 we have studied 5 Spanish families with familial nephropathy associated with hyperuricemia (FJHN). Among these families, 24 patients have been identified. All patients had some combination of hyperuricemia, gout, renal insufficiency, arterial hypertension, and reduced kidney size. The clinical presentation in the different families and in the members of the same family was heterogeneous. Allopurinol treatment did not appear to influence renal disease. From a clinical perspective, this syndrome is a distinctive interstitial nephropathy, inherited as an autosomal dominant trait, that progresses to renal failure and is not halted nor prevented by allopurinol therapy. In 2003, genetic linkage analysis in 3 of the 5 families showed linkage of FJHN to 16p 11.2. One family was not analyzed and one family did not show linkage to this region confirming the genetic heterogeneity of this syndrome. A mutation in UMOD gene was found in these 3 families as the cause of the FJHN. The mutations cluster in exon 4 and exon 5 and were point mutation that results in an amino acid change in the uromodulin or Tamm Horsfall protein. This fact allowed in 2004, the presymptomatic genetic diagnosis of an 8-years-old boy belonging to one of these 3 Spanish families. We conclude that in families with a history of renal failure and/or gout in which FJHN is suspected, UMOD mutation screening may enable a definite diagnosis. When a mutation is found, family members can be tested for a UMOD mutation and pre-symptomatic diagnosis may allow counseling to prevent or halt the progression to renal insufficiency.

A review of the implication of hypoxanthine excess in the physiopathology of Lesch-Nyhan disease.

Lesch-Nyhan disease is caused by HGprt deficiency, however, the mechanism by which enzyme deficiency leads to the severe neurological manifestations is still unknown. We hypothesized that hypoxanthine excess leads, directly or indirectly, through its action in adenosine transport, to aberrations in neuronal development. We found that hypoxanthine diminishes adenosine transport and enhances stimulation of adenosine receptors. These effects cause an imbalance between adenosine, dopamine, and serotonin receptors in HGprt deficient cells, and cells differentiated with hypoxanthine showed an increase in dopamine, adenosine and serotonin receptors expression. Hypoxanthine deregulates early neuronal differentiation increasing WNT4 and EN1 gene expression.