KIR/HLA-I mismatching and risk of relapse in paediatric patients undergoing non-haploidentical allogeneic haematopoietic stem cell transplantation

In HSCT setting, KIR-driven alloreactivity might be better predicted if the donor KIR genotype is considered in addition to the recipient HLA genotype. The prediction of NK cell alloreactivity relies on the missing ligand in the recipient, a scenario that can be found in HLA-identical and non-identical allotransplants. The aim of this study was to investigate at genetic level the prognostic impact of recipient HLA-I lacking for donor KIR on allotransplanted patients outcome. We analysed donors KIR genotype and HLA genotype of 60 paediatric patients who received related (n=15) or unrelated (n=45) transplantation. When patients were grouped based on the KIR gene type involved in the KIR/HLA-I mismatch, we did not observe any relapse in the group of patients characterized by mismatches involving only inhibitory KIR. On the contrary, all relapses were observed in patients showing at least one activating gene involved in the mismatch (p<0.05). Although the biological mechanism accounting for this putative genetic rule is still to be clarified, we suggest that a careful survey of KIR/HLA-I mismatching should be taken into account in the selection of donor in related and unrelated HSCT.     

Drug-dependence behaviour and outcome of medication-overuse headache after treatment

This study aimed at determining the causes of failure of the different proposed strategies to ensure improvement of medication-overuse headache (MOH) patients, since they have not been investigated so far, especially with regard to aspects related to cognitive and behavioural aspects of symptomatic drugs overused by them. One hundred and twenty in-patients, 82 females (68.3 %), median age 49 (42–56) years, affected by MOH were admitted to the study and treated with abrupt discontinuation of the medication overused, a 6-day in-patient detoxification regimen and an immediate start of personalized prophylactic treatment, then followed for 1 year. Leeds Dependence Questionnaire (LDQ), among all the clinical variables, was administered at baseline and at 1-year follow-up visit to assess substance dependence. Of the 120 patients enrolled, 68 (56.7 %) were successfully detoxified (Responder-group), while 52 (43.3 %) were not (Non-Responder-group). At baseline, the mean LDQ total score was slightly higher in the Non-Responder group than in the Responder group (12.08 ± 2.14 vs. 11.94 ± 1.98). Although this difference was not significant at baseline (p > 0.05), the LDQ total score was significantly different (p < 0.001) at the 1-year follow-up visit between the responder group (7.8 ± 2.3) and the Non-Responder group (12.1 ± 2.1). Moreover, the pattern of the responses of the patients in the responder group differed from that of the Non-Responder-group in the items relating to the compulsion to start, compulsion to continue, primacy of effect, constancy of state and cognitive set. The results showed that patients of the Non-Responder group showed a drug dependence pattern similar to that previously described in addicts. Conversely, in patients who positively responded to the procedure, drug-abuse behaviour seemed to be a consequence of chronic headache, reflecting the need for daily analgesic use to cope with everyday life.     

Migraine with aura in the locker room: three case reports

It is well known that physical activity can aggravate the intensity of the headache, but the pathophysiological relationship between exertion and aura is still unknown. Anecdotal reports describe episodes of migraine preceded by head trauma and visual symptoms, migraine prodrome symptoms after unusually strenuous running with no subsequent head pain or recurrent attacks of hemiplegic migraine induced only by exertion. We describe the cases of three young men with recurrent episodes of migraine with aura occurring in the locker room shortly after a football match. Since the symptoms could mimic important pathologies in approximately 10% of these of headaches, it was mandatory to exclude a secondary form of headache in these patients. Several theories exist regarding the cause of primary exertional headache, but the pathogenesis of migraine triggered by physical activity has still not been identified. The present International Classification of Headache Disorders does not mention sport/exercise-induced migraine with aura episodes as primary headache. Since there are many cases described in the literature of migraine with aura triggered only by exercise, it may be helpful to specify, in the typical aura with migraine headache comments, that in some cases it can be exclusively triggered by sport/exercise.     

Benzimidazole-2-Phenyl-Carboxamides as Dual-Target Inhibitors of BVDV Entry and Replication

Bovine viral diarrhea virus (BVDV), also known as Pestivirus A, causes severe infection mostly in cattle, but also in pigs, sheep and goats, causing huge economical losses on agricultural farms every year. The infections are actually controlled by isolation of persistently infected animals and vaccination, but no antivirals are currently available to control the spread of BVDV on farms. BVDV binds the host cell using envelope protein E2, which has only recently been targeted in the research of a potent and efficient antiviral. In contrast, RdRp has been successfully inhibited by several classes of compounds in the last few decades. As a part of an enduring antiviral research agenda, we designed a new series of derivatives that emerged from an isosteric substitution of the main scaffold in previously reported anti-BVDV compounds. Here, the new compounds were characterized and tested, where several turned out to be potent and selectively active against BVDV. The mechanism of action was thoroughly studied using a time-of-drug-addition assay and the results were validated using docking simulations.     

Visual stimulation and frequency of focal neurological symptoms engage distinctive neurocognitive resources in migraine with aura patients: a study of resting-state functional networks

IntroductionSeveral functional neuroimaging studies on healthy controls and patients with migraine with aura have shown that the activation of functional networks during visual stimulation is not restricted to the striate system, but also includes several extrastriate networks.MethodsBefore and after 4 min of visual stimulation with a checkerboard pattern, we collected functional MRI in 21 migraine with aura (MwA) patients and 18 healthy subjects (HS). For each recording session, we identified independent resting-state networks in each group and correlated network connection strength changes with clinical disease features.ResultsBefore visual stimulation, we found reduced connectivity between the default mode network and the left dorsal attention system (DAS) in MwA patients compared to HS. In HS, visual stimulation increases functional connectivity between the independent components of the bilateral DAS and the executive control network (ECN). In MwA, visual stimulation significantly improved functional connectivity between the independent component pairs salience network and DAS, and between DAS and ECN. The ECN Z-scores after visual stimulation were negatively related to the monthly frequency of aura.ConclusionsIn individuals with MwA, 4 min of visual stimulation had stronger cognitive impact than in healthy people. A higher frequency of aura may lead to a diminished ability to obtain cognitive resources to cope with transitory but important events like aura-related focal neurological symptoms.