Migraine: imaging the aura

We currently conceive of a migraine attack as originating in the brain. Triggers of an attack initiate a depolarizing neuroelectric and metabolic event likened to the spreading depression of Leao. This event activates the headache and associated features of the attack by mechanisms that remain to be determined, but appear to involve either peripheral trigeminovascular or brainstem pathways, or both. The excitability of cell membranes, perhaps partly genetically determined, is the brain's susceptibility to attacks. Factors that increase or decrease neuronal excitability constitute the threshold for triggering attacks. Using a model of visual stress-induced migraine or by studying spontaneous attacks and applying advanced imaging and neurophysiological methods, results have been obtained that support spreading neuronal inhibition as the basis of aura. This neuroelectric event is accompanied by hyperoxia of the brain, possibly associated with vasodilation. Evidence has also been obtained that the spreading cortical event can activate the subcortical centers possibly involved in nociception and associated symptoms of the migraine attack. Susceptibility to migraine attacks appears to be related to brain hyperexcitability. These newer techniques of functional neuroimaging have confirmed the primary neural basis of the migraine attack with secondary vascular changes, reconciling previous theories into a neurovascular mechanism.     

Panniculitis in childhood and adolescence

Background: The purpose of the present paper was to describe the clinical manifestations and treatment of patients with panniculitis. Methods: From January 1983 to December 2002, 4294 patients were treated for pediatric rheumatological diseases at Pediatric Rheumatology Unit, University of São Paulo, Brazil. Of these, 35 children and adolescents (0.8%) presented with panniculitis: erythema nodosum (EN) or Weber–Christian disease (WCD). Clinical characteristics, laboratory exams, biopsy of the lesion, treatment and clinical course were studied. Results: Of the 35 patients, 29 presented with EN and six with WCD, one of these with cytophagic histiocytic panniculitis. Mean age at symptom onset was 85 months (6–204 months) and the mean duration of follow up was 55 months (1–144 months). All the patients presented with inflammatory subcutaneous nodules. The patients with WCD presented with systemic manifestations and cutaneous atrophy. The principal etiologies of EN were streptococcal infection (42%), undetermined (13.5%), pulmonary tuberculosis (10%), and acute rheumatic fever (10%). Biopsy of the nodules indicated septal panniculitis in 14 patients with EN and lobular panniculitis without vasculitis in the patients with WCD, one of which had cytophagic histiocytic panniculitis. There was recurrence in 11 patients (38%) with EN and in all those with WCD. Non‐steroidal anti‐inflammatory drugs were used in 15 patients with EN and corticosteroids and/or immunosuppressive drugs in the six patients with WCD. Three patients died. Conclusions: EN is the most frequent panniculitis, with a benign course and is mainly associated with infections. WCD is a severe disease, with systemic involvement, that proceeds with cutaneous atrophy and requires the use of corticosteroids and or immunosuppressive drugs.     

Diagnosis of pulmonary embolism: Ventilation perfusion scintigraphy versus helical computed tomography pulmonary angiography

The present study compared the accuracy of ventilation perfusion scintigraphy (VQS) and CT pulmonary angiography (CTPA) for the diagnosis of pulmonary embolism. This was a prospective observational study of 112 patients with suspected pulmonary embolism (PE) who could be studied with both investigations within 24 h. Results were compared to final diagnosis at completion of 6-month follow up, using receiver operating characteristic (ROC) analysis. Pulmonary embolism was diagnosed in 27 referred patients (24%). The sensitivity and specificity of VQS and CTPA were similar to that reported from the literature. A normal VQ scan had the highest negative predictive value (100%), while a high-probability VQ scan had the highest positive predictive value (92%). There was no overall difference (area under the ROC curve (AUC)) between VQS (AUC (95% CI) = 0.82 (0.75,0.89)) and CTPA (AUC = 0.88 (0.81,0.94)) for the diagnosis of PE. Among patients with abnormal chest X-rays, CTPA (AUC 0.90 (0.83,0.97)) appeared somewhat better than VQS (AUC 0.78 (0.68,0.88)) but this difference did not reach statistical significance. In this instance, CTPA is at least as accurate as VQS and may provide an opportunity to make alternative diagnoses.     

Adjuvant therapy for resectable liver metastases: Can metastatic colorectal cancer be cured?

Surgery remains the only curative therapy for patients with liver metastases from colorectal cancer. Unfortunately, only a minority of patients are candidates. The use of clinical prognostic indicators and computer programs, such as OncoSurge, may help to identify optimal candidates. Neoadjuvant chemotherapy may render previously ineligible patient candidates for curative surgery after downsizing. Neoadjuvant chemotherapy is associated with histopathologic changes of the liver, and the effect of such changes on survival is unclear. Promising results have been seen with chemotherapy infused through the hepatic artery in conjunction with systemic chemotherapy in the neoadjuvant and adjuvant settings. Adjuvant therapy with oxaliplatin-or irinotecan-based regimens after resection of liver metastases is generally recommended. Individuals should be encouraged to participate in clinical trials to help clarify the role and optimal sequencing of systemic chemotherapy, targeted agents, local therapies, and surgery for patients with hepatic metastases from colorectal cancer.     

Definition of a saxitoxin (STX) binding code enables discovery and characterization of the anuran saxiphilin family

American bullfrog (Rana castesbeiana) saxiphilin (RcSxph) is a high-affinity “toxin sponge” protein thought to prevent intoxication by saxitoxin (STX), a lethal bis-guanidinium neurotoxin that causes paralytic shellfish poisoning (PSP) by blocking voltage-gated sodium channels (Na_Vs). How specific RcSxph interactions contribute to STX binding has not been defined and whether other organisms have similar proteins is unclear. Here, we use mutagenesis, ligand binding, and structural studies to define the energetic basis of Sxph:STX recognition. The resultant STX “recognition code” enabled engineering of RcSxph to improve its ability to rescue Na_Vs from STX and facilitated discovery of 10 new frog and toad Sxphs. Definition of the STX binding code and Sxph family expansion among diverse anurans separated by ∼140 My of evolution provides a molecular basis for understanding the roles of toxin sponge proteins in toxin resistance and for developing novel proteins to sense or neutralize STX and related PSP toxins.

Saxitoxin (STX), one of the most potent nonpeptidyl neurotoxins, blocks the bioelectrical signals in nerve and muscle required for life by inhibiting select voltage-gated sodium channel (Na_V) isoforms (1–3). Cyanobacteria and dinoflagellate species associated with oceanic red tides produce this bis-guanidinium small molecule and its congeners, whose accumulation in seafood can cause paralytic shellfish poisoning (PSP), a commercial fishing and public health hazard of growing importance due to climate change (1, 3–5). Its lethality has also earned STX the unusual distinction of being the only marine toxin declared a chemical weapon (1, 3). Select vertebrates, particularly frogs, resist STX poisoning (6–9), a property that is thought to rely on the ability of the soluble “toxin sponge” protein saxiphilin (Sxph) to sequester STX (8, 9). Recent structural studies (10) defined the molecular architecture of the American bullfrog [Rana (Lithobates) castesbeiana] Sxph (RcSxph) (8, 11–14) showing that this 91-kDa soluble, transferrin-related protein from frog heart and plasma has a single, high-affinity STX binding site on its C lobe. Remarkably, even though RcSxph and Na_Vs are unrelated, both engage STX through similar types of interactions (10). This structural convergence raises the possibility that determination of the factors that underlie the high-affinity Sxph:STX interaction could provide a generalizable molecular recognition code for STX that would enable the identification or engineering of STX binding sites in natural and designed proteins.To characterize RcSxph:STX interactions in detail, we developed a suite of assays comprising thermofluor (TF) measurements of ligand-induced changes in RcSxph stability, fluorescence polarization (FP) binding to a fluorescein-labeled STX, and isothermal titration calorimetry (ITC). We paired these assays with a scanning mutagenesis strategy (15, 16) to dissect the energetic contributions of RcSxph STX binding pocket residues. These studies show that the core RcSxph STX recognition code comprises two “hot spot” triads. One engages the STX tricyclic bis-guanidinium core through a pair of carboxylate groups and a cation–π interaction (17) in a manner that underscores the convergent STX recognition strategies shared by RcSxph and Na_Vs (17–22). The second triad largely interacts with the C13 carbamate group of STX and is the site of interactions that can enhance STX binding affinity and the ability of RcSxph to act as a “toxin sponge” that can reverse the effects of STX inhibition of Na_Vs (8, 9).Although Sxph-like STX binding activity has been reported in extracts from diverse organisms including arthropods (13), amphibians (11, 13, 23), fish (13), and reptiles (13), the molecular origins of this activity have remained obscure. Definition of the RcSxph STX recognition code enabled identification of 10 new Sxphs from diverse frogs and toads. This substantial enlargement of the Sxph family beyond RcSxph and the previously identified High Himalaya frog (Nanorana parkeri) Sxph (NpSxph) (10) reveals a varied STX binding pocket that surrounds a conserved core of “hot spot” positions. Comparison of the new Sxph family members further identifies dramatic differences in the number of thyroglobulin (Thy1) domains inserted into the modified transferrin fold upon which the Sxph family is built. Biochemical characterization of NpSxph, Oophaga sylvatica Sxph (OsSxph) (24), Mantella aurantiaca Sxph (MaSxph), and Ranitomeya imitator Sxph (RiSxph), together with structural determination of NpSxph, alone and as STX complexes, shows that the different Sxphs share the capacity to form high-affinity STX complexes and that binding site preorganization (10) is a critical factor for tight STX association. Together, these studies establish an STX molecular recognition code that provides a template for understanding how diverse STX binding proteins engage the toxin and its congeners and uncover that Sxph family members are abundantly found in the most varied and widespread group of amphibians, the anurans. This knowledge and suite of diverse Sxphs, conserved among anuran families separated by at least 140 My of evolution (25), provide a starting point for defining the physiological roles of Sxph in toxin resistance (9, 24, 26), should facilitate identification or design of other STX binding proteins, and may enable the development of new biologics to detect or neutralize STX and related PSPs.     

Development and validation in Ecuador of the EPD Questionnaire,a diabetes‐specific patient‐reported experience and outcome measure: A mixed‐methods study

IntroductionThe global prevalence of diabetes in 2019 in adults was estimated to be 9.3%. This study developed in Ecuador, for the first time, instruments to assess patient‐reported outcomes and experiences.MethodsThe Experiences of the Person with Diabetes (EPD) Questionnaire is a diabetes‐specific instrument. A mixed‐methods study was conducted. First, a qualitative item development phase that included four focus groups and six semi‐structured interviews with patients was conducted in different rural and urban areas of Ecuador to obtain information on culture, beliefs, demographics, diet and social perspectives. A second quantitative phase for psychometric validation was carried out in primary care settings of rural and urban areas of Ecuador.ResultsForty‐two and four hundred and eighty‐nine participants were included in each phase, respectively. The item development phase resulted in a questionnaire of 44 items (23 for perceived outcomes and 21 for experiences). In the validation study, most participants were women (58%) and from urban areas (57%). Exploratory factor analysis revealed three dimensions for each instrument. Outcomes instrument dimensions were symptoms and burnout, worries and fears and social limitations. Experiences instrument dimensions were information, patient‐centred care and care delivery. Cronbach''s α values of the total score and dimensions were high, ranging between .81 and .93 in both instruments. Confirmatory factor analysis showed an acceptable fit of the data.ConclusionThe EPD Questionnaire is probably the first instrument developed to assess patient‐reported experiences and perceived outcomes in a middle‐income country that included patients to capture all dimensions relevant for the intended population. Its psychometric properties are robust and could provide valuable information for clinicians and policymakers in the region.Patient or Public ContributionThe development of these instruments has taken into consideration patients and the public since their conception. A qualitative approach gathered relevant information related to the cultural, social and economic burden of different populations in Ecuador. Before validation, a pilot test was carried out with users of the National Health Services to obtain their perspectives and insights of the developed instrument. Finally, during the data analysis, we have given special consideration to social variables such as rural and urban populations.