Verb generation for presurgical mapping: Gaining specificity

Verb generation is among the most frequently used tasks in presurgical mapping. Because this task involves many processes, the overall brain effects are not specific. While it is necessary to identify the whole network involving noun comprehension or semantic retrieval and lexical selection to produce the verb, isolation of those components is also crucial. Here, we present data from four patients undergoing presurgical brain mapping. The study implied a reanalysis of magnetoencephalography data with a recategorization of the used items. It aimed to extract the task component that relies on the inferior frontal gyrus (IFG). The task could be applied with higher specificity when targeting frontal areas. For that, we based item classification on the selection demands imposed by the noun. It is a robust finding that the IFG carries out this selection and that a quantitative index can be calculated for each noun, which depends on the selection effort (Proceedings of the National Academy of Sciences of the United States of America, 1997; 94(26):14792–14797, Proceedings of the National Academy of Sciences of the United States of America, 1998; 95(26):15855–15860). Data showed focality and specificity, with a correlation between this derived index and source activations in the inferior frontal gyrus for all patients. Strikingly, we detected when the right‐hemisphere homologue area was involved in the selection process in two patients showing reorganization or language right lateralization. The present data are a step towards a dissection of broad specific tasks frequently used in presurgical protocols

High prolactin levels in dihydropteridine reductase deficiency: A sign of therapy failure or additional pathology?

We report the case of a 22-year-old man with a diagnosis of dihydropteridine reductase (DHPR) deficiency who progressively developed movement disorders and epilepsy. Despite L-Dopa supplementation the patient continued to show high prolactin levels, with a discrepancy between the neurological clinical picture and the hormonal biochemical levels. For this reason, other potential causes were ruled out by performing a cerebral magnetic resonance imaging, which demonstrated a solid lesion in the pituitary gland strongly suggestive of a prolactinoma. As the association between metabolic disorders affecting biogenic amine synthesis and prolactinoma has not been previously reported in humans, this report suggests that a critical evaluation of the use of prolactin as a guide for therapy dosage should be made in patients with DHPR deficiency disorders

Menopause, the cardiovascular risk factor homocysteine, and the effects of treatment.

Since the identification of homocysteine (Hcy) as a risk factor for cardiovascular disease, it has been the subject of much research. As with other cardiovascular risk factors, a gender difference exists for Hcy. Plasma levels are lower in women of reproductive age than in men and postmenopausal women. This has led to the hypothesis that the increased risk of cardiovascular disease documented in postmenopausal women may be related to the increase in Hcy levels. Factors affecting total plasma levels of Hcy include genetic factors, nutritional factors, and lifestyle. Many studies appear to support the ability of estrogen replacement therapy to significantly lower both basal levels of Hcy and levels following methionine loading. A mean reduction of 10-15% in Hcy levels after 6 months of hormone therapy has been reported. Similarly, raloxifene and tamoxifen and low-dose folic acid administration induce reductions in plasma Hcy levels of the same degree observed for hormone therapy. The reduction occurs after a few months of therapy and is sustained, suggesting the potential for cardioprotective effects. Although there is a positive effect of estrogen therapy and hormone therapy on Hcy levels, recent studies do not recommend the use of estrogen or hormone replacement therapy for the primary or secondary prevention of cardiovascular disease. Further research is therefore needed to identify strategies to maximize the efficacy of hormone replacement therapy, while minimizing the risk

Total laparoscopic hysterectomy: Overtreatment for misdiagnosed organic cause or undertreatment for idiopathic chronic pelvic pain?

Background: Chronic pelvic pain (CPP) is considered a symptom but also a syndrome with misunderstood pathophysiology and treatment options ranging from conservative management to opioid analgesia and surgical intervention. The aim of this study was to evaluate the role of gynecological surgery in modifying presurgical pain status and reducing the postoperative analgesic use of patients suffering CPP. The second aim of the study was to analyze intraoperative and histological differences in patients who benefited from surgery versus those without benefit. Methods: An observational study was conducted in 16 fertile women affected by CPP, treated by total laparoscopic hysterectomy (TLH) to solve their pelvic pain. In 7 cases, undetected pelvic endometriosis was found. Results: A complete resolution of preoperative pain symptoms (score 0) occurred in 9 patients (56.2%), an occasional pelvic discomfort (score 1) in 2 cases (12.5%), 2 patients reported minimal benefit of pelvic pain (score 2), while in 3 cases, severe pain persisted (score 3). The correlation between intraoperative/histological features and reported symptoms after surgery showed that 7 of 9 patients (77.7%) who benefited from surgery were affected by an organic cause; while 5 women with minimal or no benefits from the surgery did not have any organic disease (idiopathic CPP). Conclusions: If conservative treatment fails to treat CPP, investigative laparoscopy represents a necessary step to discriminate patients with misdiagnosed organic from idiopathic CPP, selecting those who will potentially benefit from hysterectomy. The role of concomitant appendectomy needs to be defined in surgical treatment of idiopathic CPP

Executive Functions and Attention in Childhood Epilepsies: A Neuropsychological Hallmark of Dysfunction?

Objective: Patients with epilepsy are at risk for several lifetime problems, in which neuropsychological impairments may represent an impacting factor. We evaluated the neuropsychological functions in children suffering from three main epilepsy categories. Further, we analyzed the longitudinal evolution of the neuropsychological profile over time. Methods: Patients undergoing neuropsychological evaluation at our Department from 2012 to 2018 were identified retrospectively. We selected patients aged 6-16 years and with at least two evaluations. Three epilepsy categories were considered: focal/structural, focal self-limited, and idiopathic generalized. Each evaluation included the same structured assessment of main neuropsychological domains. The effect of the epilepsy category, illness duration, seizure status, and medication was computed in multilevel models. Results: We identified 103 patients (focal self-limited = 27; focal/structural = 51; and idiopathic generalized = 25), for 233 evaluations. The majority of deficits were reported in attention and executive functions (>30% of patients); the results were dichotomized to obtain global indexes. Multilevel models showed a trend toward statistical significance of category of epilepsy on the global executive index and of illness duration on global attention index. Illness duration predicted the scores of executive and attention tasks, while category and medication predicted executive task performance. Focal/structural epilepsies mostly affected the executive domain, with deficits persisting over time. By contrast, an ameliorative effect of illness duration for attention was documented in all epilepsies. Conclusions: This study offers lacking information about the evolution of deficits in time, the role of epilepsy category, and possible psychological implications for high-order cognitive skills, central in several social and academic problems

Bioactive compounds of Crocus sativus L. and their semisynthetic derivatives as promising anti-Helicobacter pylori, anti-malarial and anti-leishmanial agents

Crocus sativus L. is known in herbal medicine for the various pharmacological effects of its components, but no data are found in literature about its biological properties toward Helicobacter pylori, Plasmodium spp. and Leishmania spp. In this work, the potential anti-bacterial and anti-parasitic effects of crocin and safranal, two important bioactive components in C. sativus, were explored, and also some semi-synthetic derivatives of safranal were tested in order to establish which modifications in the chemical structure could improve the biological activity. According to our promising results, we virtually screened our compounds by means of molecular modeling studies against the main H. pylori enzymes in order to unravel their putative mechanism of action

Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication

Objective: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients. Methods: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. Results: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. Significance: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication

Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy

Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain