The European Rare Disease Network for HHT Frameworks for management of hereditary haemorrhagic telangiectasia in general and speciality care.

Hereditary haemorrhagic telangiectasia (HHT) is a complex, multisystemic vascular dysplasia affecting approximately 85,000 European Citizens. In 2016, eight founding centres operating within 6 countries, set up a working group dedicated to HHT within what became the European Reference Network on Rare Multisystemic Vascular Diseases. By launch, combined experience exceeded 10,000 HHT patients, and Chairs representing 7 separate specialties provided a median of 24 years' experience in HHT. Integrated were expert patients who focused discussions on the patient experience. Following a 2016-2017 survey to capture priorities, and underpinned by more than 40 monthly meetings, and new data acquisitions, VASCERN HHT generated position statements that distinguish expert HHT care from non-expert HHT practice. Leadership was by specialists in the relevant sub-discipline(s), and 100% consensus was required amongst all clinicians before statements were published or disseminated. One major set of outputs targeted all healthcare professionals and their HHT patients, and include the new Orphanet definition; Do's and Don'ts for common situations; Outcome Measures suitable for all consultations; COVID-19; and anticoagulation. The second output set span aspects of vascular pathophysiology where greater understanding will assist organ-specific specialist clinicians to provide more informed care to HHT patients. These cover cerebral vascular malformations and screening; mucocutaneous telangiectasia and differential diagnosis; anti-angiogenic therapies; circulatory interplays between anaemia and arteriovenous malformations; and microbiological strategies to counteract loss of normal pulmonary capillary function. Overall, the integrated outputs, and documented current practices, provide frameworks for approaches that augment the health and safety of HHT patients in diverse health-care settings.

The Spectrum of Congenital Central Nervous System Anomalies Among Stillborn: An Autopsy Based Study.

BACKGROUND: Congenital central nervous system (CNS) anomalies are the structural or functional abnormalities of the brain and spinal cord that occur during the intrauterine developmental process. PURPOSE: The present study aims to detect the prevalence of congenital CNS anomalies among stillborn fetuses, the association between congenital anomalies and maternal factors, and also the association between autopsy and ultrasound findings. METHODS: This study was conducted on 50 stillborn fetuses, obtained from the Department of Obstetrics and Gynecology at JSS Medical College and Hospital, Mysuru. The fetuses were fixed in 10% formalin and autopsies were performed as per the standard fetal autopsy protocol. The congenital CNS anomalies were studied in detail. RESULTS: CNS anomalies were the most common congenital anomalies observed. Out of the total 50 stillborn fetuses studied, CNS anomalies were found in 17 fetuses and their occurrence was more common among male stillborn than females. Meningomyelocele was the most common anomaly, followed by anencephaly. The other anomalies documented were meningocele, encephalocele, meningoencephalocele, agenesis of the corpus callosum, craniorachischisis, bifid cerebellum with hypoplastic vermis, holoprosencephaly, and sirenomelia.Fisher's exact test showed a significant association between maternal hypothyroidism and congenital CNS anomalies (P < .05). The autopsy confirmed the ultrasound findings in 40 (80%) fetuses. There were significant additional findings observed in seven (14%) fetal autopsies and ultrasound diagnosis completely changed in three (6%) cases, after the final autopsy procedure. CONCLUSION: The fetal autopsy is the single most directly evident investigation, which gives information that changes or significantly improves the clinical diagnosis. A multidisciplinary holistic approach toward pregnancy will help to detect any kind of abnormality in the fetus and thus to take a timely decision toward the management.

Diffusion tensor imaging reveals changes in microstructural integrity along compressed nerve roots that correlate with chronic pain symptoms and motor deficiencies in elderly stenosis patients.

Age-related degenerative changes in the lumbar spine frequently result in nerve root compression causing severe pain and disability. Given the increasing incidence of lumbar spinal disorders in the aging population and the discrepancies between the use of current diagnostic imaging tools and clinical symptoms, novel methods of nerve root assessment are needed. We investigated elderly patients with stenosis at L4-L5 or L5-S1 levels. Diffusion tensor imaging (DTI) was used to quantify microstructure in compressed L5 nerve roots and investigate relationships to clinical symptoms and motor neurophysiology. DTI metrics (i.e. FA, MD, AD and RD) were measured at proximal, mid and distal segments along compressed (i.e. L5) and intact (i.e. L4 or S1) nerve roots. FA was significantly reduced in compressed nerve roots and MD, AD and RD were significantly elevated in the most proximal segment of the nerve root studied. FA was significantly correlated with electrophysiological measures of root function: minimum F-wave latency and peripheral motor conduction time (PMCT). In addition, FA along the compressed root also correlated with leg pain and depression score. There was also a relationship between RD and anxiety, leg pain and disability score and AD correlated with depression score. Taken together, these data show that DTI metrics are sensitive to nerve root compression in patients with stenosis as a result of age-related lumbar degeneration. Critically, they show that the changes in microstructural integrity along compressed L5 nerve roots are closely related to a number of clinical symptoms associated with the development of chronic pain as well as neurophysiological assessments of motor function. These inherent relationships between nerve root damage and phenotype suggest that the use DTI is a promising method as a way to stratify treatment selection and predict outcomes.

Relationships between the integrity and function of lumbar nerve roots as assessed by diffusion tensor imaging and neurophysiology.

PURPOSE: Diffusion tensor imaging (DTI) has shown promise in the measurement of peripheral nerve integrity, although the optimal way to apply the technique for the study of lumbar spinal nerves is unclear. The aims of this study are to use an improved DTI acquisition to investigate lumbar nerve root integrity and correlate this with functional measures using neurophysiology. METHODS: Twenty healthy volunteers underwent 3 T DTI of the L5/S1 area. Regions of interest were applied to L5 and S1 nerve roots, and DTI metrics (fractional anisotropy, mean, axial and radial diffusivity) were derived. Neurophysiological measures were obtained from muscles innervated by L5/S1 nerves; these included the slope of motor-evoked potential input-output curves, F-wave latency, maximal motor response, and central and peripheral motor conduction times. RESULTS: DTI metrics were similar between the left and right sides and between vertebral levels. Conversely, significant differences in DTI measures were seen along the course of the nerves. Regression analyses revealed that DTI metrics of the L5 nerve correlated with neurophysiological measures from the muscle innervated by it. CONCLUSION: The current findings suggest that DTI has the potential to be used for assessing lumbar spinal nerve integrity and that parameters derived from DTI provide quantitative information which reflects their function.

Novel strategies for targeting innate immune responses to influenza.

We previously reported that TLR4(-/-) mice are refractory to mouse-adapted A/PR/8/34 (PR8) influenza-induced lethality and that therapeutic administration of the TLR4 antagonist Eritoran blocked PR8-induced lethality and acute lung injury (ALI) when given starting 2 days post infection. Herein we extend these findings: anti-TLR4- or -TLR2-specific IgG therapy also conferred significant protection of wild-type (WT) mice from lethal PR8 infection. If treatment is initiated 3 h before PR8 infection and continued daily for 4 days, Eritoran failed to protect WT and TLR4(-/-) mice, implying that Eritoran must block a virus-induced, non-TLR4 signal that is required for protection. Mechanistically, we determined that (i) Eritoran blocks high-mobility group B1 (HMGB1)-mediated, TLR4-dependent signaling in vitro and circulating HMGB1 in vivo, and an HMGB1 inhibitor protects against PR8; (ii) Eritoran inhibits pulmonary lung edema associated with ALI; (iii) interleukin (IL)-1ß contributes significantly to PR8-induced lethality, as evidenced by partial protection by IL-1 receptor antagonist (IL-1Ra) therapy. Synergistic protection against PR8-induced lethality was achieved when Eritoran and the antiviral drug oseltamivir were administered starting 4 days post infection. Eritoran treatment does not prevent development of an adaptive immune response to subsequent PR8 challenge. Overall, our data support the potential of a host-targeted therapeutic approach to influenza infection.

3-(2-Chloro-3-hy-droxy-4-meth-oxy-phen-yl)-1-(4,5-dimeth-oxy-2-methyl-phen-yl)prop-2-en-1-one.

The title compound, C(19)H(19)ClO(5), is a chloro derivative of a biologically significant chalcone family. The mean plane of the two substituted benzene rings are twisted by 55.33 (8)° with respect to each other. An intra-molecular C-H⋯Cl hydrogen bond generates an S(5) graph-set motif. In the crystal, a bifurcated O-H⋯(O,O) hydrogen bond leads to an R(1) (2)(5) graph-set motif and to the formation of zigzag chains propagating along the c-axis direction. A weak π-π inter-action involving the methyl-phenyl rings [centroid-centroid distance = 3.8185 (10) Å] and C-H⋯π inter-actions also occur.

The prevalence of traumatic dental injuries to permanent anterior teeth and its relation with predisposing risk factors among 8-13 years school children of Vadodara city: an epidemiological study.

BACKGROUND AND OBJECTIVE: dental trauma is an irreversible pathology that after occurrence is characterized by life-long debilitating effects. The objectives of this study were to measure the prevalence of anterior teeth fracture and their association with predisposing factors such as lip coverage, molar relationship, overjet, and variables such as age, sex, cause, and place of trauma. MATERIALS AND METHODS: an epidemiological cross-sectional study was carried out among 3708 school children aged 8-13 years in the Vadodara city. All children completed a questionnaire related to history of trauma to their anterior teeth after which they were examined for lip competence, Angle's molar relationship amount of overjet and nature of trauma sustained. The results were statistically analyzed using the prevalence test, Chi-square test, and Mantel-Haenszel Common Odds Ratio. RESULTS: the prevalence of traumatic injuries was 8.79% and the ratio of boys: girl's was 1.28:1. Inadequate lip coverage group sustained about five times more injuries than the adequate lip coverage group (P = 0.000, OR= 5.407). The maximum traumatic injuries were seen in children having Angle Class II Div 1 molar relationship and/or overjet greater than 5.5 mm and was statistically significant (P<0.05). Maximum number of injuries occurred at 9 years of age. The most predominant injuries were enamel fractures, the most common place for occurrence was home and fall against object, the most frequent cause. CONCLUSION: the prevalence of dental injuries in the Vadodara city is high and it has a great potential to be considered as an emerging public health problem.

Making a jigsaw puzzle in 10 minutes: is case management feasible in general practice?

Background Case management has been advocated as a method of optimising the care of patients with complex problems and reducing inappropriate use of hospital services, but its impact to date has been limited. It is not known whether case management earlier in the development of complex problems will be more effective. Aim To develop a case management protocol usable in general practice. Design Co-designed by practitioners using a technology development approach. Setting General practices and community nursing teams in one primary care trust (PCT). Method Nominal group techniques applied to six multidisciplinary workshops held over nine months, in order to design and refine a case management protocol. Then field testing of the protocol with selected patients in four practices. Results A modular case management protocol has been designed that can be used in routine practice and completed over successive consultations. The protocol asks the practitioner and patient about their different perspectives on need, and about mental health, social care needs, nutritional status, vision and hearing, bone fragility, pain, continence and where appropriate end-of-life plans. An electronic version can be partially populated automatically, from the existing medical record. Field testing suggests that a paper version can also be used as a patient-held record for other professionals to use. Conclusion This study has created a model of case management for general practice that appears to be useable in general practice. A wider feasibility study is now needed to test uptake of the protocol by practices.

Primary cutaneous large B-cell lymphoma shows activation of nuclear factor kappa B and low incidence of Epstein-Barr virus.

Primary cutaneous lymphomas are defined as lymphomas, which are present in the skin without evidence of extracutaneous disease at the time of diagnosis. Primary cutaneous large B-cell lymphoma (PCLBCL) is a subtype of primary cutaneous B-cell lymphoma with a female predominance, occurring in elderly patients and known to have unfavorable prognosis. We evaluated 10 cases of PCLBCL in immunocompetent patients between 2005 and 2008. A panel of immunoperoxidase stains; CD3, CD10, CD20, BCL2, BCL6, and MUM1 were performed on all cases. Nuclear factor kappa B (NF-kappaB) pathway activation was evaluated using an immunostain for P65. The presence of Epstein-Barr virus (EBV) was assessed using Epstein-Barr virus encoded RNA (EBER) in situ hybridization probe. All cases were CD20 positive and CD3 negative. CD10, BCL6, BCL2, and MUM1 were positive in 4/10 (40%), 6/10 (60%), 7/10 (70%), and 7/10 (70%) cases, respectively. NF-kappaB activation was detected in 7/10 (70%) cases. One (10%) case was positive for EBV by in situ hybridization. Interestingly, the EBV positive case was also positive for MUM1 and negative for CD10, indicating an activated immunophenotype. In conclusion, majority of PCLBCL shows activation of NF-kappaB pathway with a low incidence of EBV.

Distinct frontal systems for response inhibition, attentional capture, and error processing.

Stopping an action in response to an unexpected event requires both that the event is attended to, and that the action is inhibited. Previous neuroimaging investigations of stopping have failed to adequately separate these cognitive elements. Here we used a version of the widely used Stop Signal Task that controls for the attentional capture of stop signals. This allowed us to fractionate the contributions of frontal regions, including the right inferior frontal gyrus and medial frontal cortex, to attentional capture, response inhibition, and error processing. A ventral attentional system, including the right inferior frontal gyrus, has been shown to respond to unexpected stimuli. In line with this evidence, we reasoned that lateral frontal regions support attentional capture, whereas medial frontal regions, including the presupplementary motor area (pre-SMA), actually inhibit the ongoing action. We tested this hypothesis by contrasting the brain networks associated with the presentation of unexpected stimuli against those associated with outright stopping. Functional MRI images were obtained in 26 healthy volunteers. Successful stopping was associated with activation of the right inferior frontal gyrus, as well as the pre-SMA. However, only activation of the pre-SMA differentiated stopping from a high-level baseline that controlled for attentional capture. As expected, unsuccessful attempts at stopping activated the anterior cingulate cortex. In keeping with work in nonhuman primates these findings demonstrate that successful motor inhibition is specifically associated with pre-SMA activation.

Unusual clivus lesion demonstrating extramedullary haematopoiesis: case report.

INTRODUCTION: An unusual clivus mass is reported, following investigation of memory disturbance and headaches in a patient with beta thalassaemia and sickle cell disease. This lesion proved to be a site of extramedullary haematopoiesis. RADIOLOGICAL FINDINGS: Computed tomography demonstrated a 2 cm mass at the base of the sphenoid. However, magnetic resonance imaging showed little bony expansion, and the differential diagnosis included chordoma, dermoid cyst and fibrodysplasia. HISTOLOGICAL FINDINGS: Examination of the biopsy showed the presence of bone marrow demonstrating erythroid hyperplasia and small aggregates of B-cell lymphocytes. The features were considered compatible with erythroid hyperplasia associated with haemolytic anaemia. MANAGEMENT: The patient was reassured that she did not have a neoplastic lesion, and was referred back to the haematologists for further management of her sickling beta thalassaemia. CONCLUSIONS: Extramedullary haematopoiesis occurs outside the reticuloendothelial system in response to haemolytic anaemia. Extramedullary haematopoiesis causing a clivus mass is an unusual ENT presentation. Such haematopoiesis is occasionally seen in the calvarial skull, but this is the first report of this process occurring in the anterior skull base, to our knowledge.

Trimethoprim related Hyperkalaemia in a patient with Renal Tubular Acidosis Type 4.

Hyperkalaemia is a common, treatable, medical emergency, often with an iatrogenic cause. This case illustrates the vulnerability of patients with pre-existing renal tubular acidosis type 4 to medications that further inhibit renin-aldosterone action. The case also illustrates the danger of keeping entirely separate case notes between different hospital disciplines.

Erythrodermic syringotropic cutaneous T-cell lymphoma.

Syringotropic cutaneous T-cell lymphoma (CTCL) is a rare localized variant of CTCL, characterized histologically by eccrine gland and ductal hyperplasia surrounded by a dense syringotropic lymphocytic infiltrate. Previously reported only in men, we describe the first woman with syringotropic CTCL. Unusually, she presented with erythroderma, cutaneous nodules, poikilodermatous patches, widespread alopecia and lymphadenopathy.

Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), the incidence and severity of toxicities, and the pharmacokinetics of lobradimil administered intravenously over 10 min in combination with carboplatin in children with refractory brain tumors. METHODS: A group of 25 children with primary brain tumors received carboplatin and lobradimil on two consecutive days every 28 days. The 10-min lobradimil infusion began 5 min before the end of the carboplatin infusion. Four lobradimil dose levels (100, 300, 450 and 600 ng/kg ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carboplatin was adaptively dosed based on the glomerular filtration rate to achieve a target plasma area under the concentration-time curve (AUC) of 7.0 mg min/ml per course (5.0 mg min/ml for patients who had previously received craniospinal radiation or myeloablative chemotherapy). RESULTS: Lobradimil toxicity was immediate, tolerable and rapidly reversible. The most frequent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during the lobradimil infusion. The incidence and severity of lobradimil toxicities were not dose-related and the lobradimil dose was not escalated beyond the 600 ng/kg IBW dose level. Two patients had partial responses and ten patients had stable disease. Myelosuppression (thrombocytopenia more prominent than neutropenia) was the primary toxicity attributed to carboplatin. Lobradimil pharmacokinetics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability. CONCLUSIONS: The combination of carboplatin and lobradimil is safe and tolerable. An MTD for lobradimil was not defined because toxicity was not dose-related. The recommended pediatric phase II dose of lobradimil is 600 ng/kg IBW.

Multimodality MR imaging depiction of hemodynamic changes and cerebral ischemia in subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) is a common and serious neurologic emergent condition. We tested the hypothesis that multimodality MR imaging depicts changes in cerebral blood flow SAH, before any surgical or endovascular intervention, and that the frequency of these changes increases with time after ictus. METHODS: We prospectively examined 37 patients with suspected SAH and three with symptoms of acute stroke but who subsequently had SAH. Routine CT and multimodality MR imaging were performed within 18 h of presentation. Standard MR imaging, diffusion-weighted MR imaging, time-of-flight MR angiography, and dynamic first-pass gadolinium-enhanced MR perfusion imaging were performed. Images were reviewed for abnormalities in cerebral blood flow, ischemia, and infarction. Nine patients did not have SAH at CT and CSF investigations. Of 31 patients with proved SAH, 13 were examined during the acute stage (within 4 d of ictus) and 18, during the subacute stage (4-14 d after ictus). RESULTS: MR imaging showed alteration in cerebral blood flow parameters in 16 of 31 patients before surgery or endovascular treatment. The frequency of blood flow changes and associated complications increased with worsening clinical grade and increasing time after ictus. CONCLUSION: Multimodality MR imaging provides information not available from CT in patients with SAH. MR imaging shows oligemic and ischemic areas in SAH before surgery or endovascular treatment. MR imaging is a simple noninvasive method of assessing cerebral blood flow and its complications in SAH. It can be performed in a clinical environment.

Imaging infection with LeuTech.

LeuTech is a 99Tcm labelled, anti-CD15, IgM, murine monoclonal antibody shown to have high affinity (Kd = 10(-11) M) for CD15 receptors (5.1 x 10(5)/cell) expressed on human neutrophils. LeuTech was injected directly, intravenously, and its efficacy in imaging infection in 46 consecutive patients was determined. Human anti-mouse antibody (HAMA) response was examined in 30 normal volunteers using a standard LeuTech dose reconstituted with decayed 99Tcm solution. There were 38 true positive, six true negative, and two false negative scans. Of the 38 positive images, 33 (92%) were positive within 10 min after injection of LeuTech. LeuTech accuracy in this group of patients was 96%, sensitivity 95%, specificity 100%, positive predictive value (PPV) 100%, and negative predictive value (NPV) 75%. No elevation of the HAMA titre was observed in any of the 30 normal volunteers and no adverse reaction was noted in any patient. LeuTech is a highly promising agent for rapid imaging of infectious foci.

Spontaneous obliteration of pial arteriovenous malformations: a review of 27 cases.

BACKGROUND AND PURPOSE: Brain arteriovenous malformations (AVMs) occur in approximately 0.14% of the population. The most common presentations are hemorrhage (50%) and seizures (25%). Although they are congenital abnormalities, their angioarchitecture may vary over time. A rare but well-recognized phenomenon of AVMs is that of spontaneous obliteration. It is not known what factors predispose to spontaneous obliteration. The purpose of our study was to determine whether spontaneous thrombosis of AVMs can be predicted by their angioarchitecture and whether there is any risk of recurrence once obliteration has occurred. METHODS: We retrospectively reviewed the angiographic and cross-sectional imaging data amassed over an 18-year period, including follow-up imaging studies and mail surveys of referring and family physicians. A control group was obtained from contemporaneous AVMs of a similar size. RESULTS: We identified 28 cases of spontaneous obliteration in a series of 2162 patients. The mean time between initial diagnostic angiography and angiographic obliteration was 10 months, during which time there was no intervention and no history of repeat hemorrhage; nor had hemorrhage recurred during the follow-up period (mean, 53 months). Most of the AVMs were deep (22/27) with only one draining vein (21/27) and few feeding arteries. In more than half the cases (15/27) drainage was exclusively into the superficial venous system. CONCLUSION: Spontaneous obliteration is rare (1.3%). Common features include hemorrhagic presentation and few arterial feeding vessels. Although we found no instance of repeat hemorrhage during the follow-up period, AVMs can recanalize, and follow-up is therefore recommended.