Autosomal dominant lateral temporal lobe epilepsy associated with a novel reelin mutation

Aims. Reelin mutations are responsible for a minority of families with autosomal dominant lateral temporal lobe epilepsy. Here, we report a novel nuclear family with distinct clinical and neuroradiological findings. Methods. We studied the proband and her mother by means of EEG, video‐EEG, 3T MRI, FDG‐PET and genetic testing. Results. Both patients had a focal drug‐resistant epilepsy with onset at the age of 16 and focal seizures with typical auditory features combined with fear, followed by loss of contact or evolving to bilateral tonic‐clonic seizures. The proband's ictal EEG showed clear left temporal seizure onset, and cerebral MRI revealed subtle left temporal changes (mild hypotrophy, slight blurring of the white and grey matter and hyperintensity) with corresponding left temporal mesial focal hypometabolism on FDG‐PET. Genetic testing identified a missense variant, c.6631C>T (p.Arg2211Cys), in reelin repeat #5 in both patients, which markedly affected the secretion of the protein. Conclusion. The data from this family support previous findings indicating that reelin mutations are a cause of autosomal dominant lateral temporal lobe epilepsy which has a clinical spectrum that may also encompass drug‐resistant epilepsy associated with mild MRI temporal changes.     

Endometriosis: current and future medical therapies

Endometriosis is a chronic inflammatory disease that responds to steroidal manipulation. Creation of a steady hormonal environment with inhibition of ovulation temporarily suppresses the ectopic implants and reduces the inflammatory status as well as the associated pain symptoms. Pharmacological management of endometriosis must be set within the framework of long-term therapeutic strategies. As the available drugs are not curative, treatments will need to be administered for years or until women desire a pregnancy. The various therapies studied have shown similar efficacy. Consequently, based on a more favourable profile in terms of safety, tolerability and cost, combined oral contraceptives and progestins should be considered as the first-line option, both as an alternative to surgery and as a postoperative adjuvant measure. Gonadotrophin-releasing hormone analogues, danazol and gestrinone should be used when progestins and oral contraceptives fail, are not tolerated or are contra-indicated. Future therapies for endometriosis must compare favourably with existing drugs before hypothesizing their implementation in current practice. Medical treatment is not indicated in women seeking conception because reproductive prognosis is not ameliorated.     

Macronutrients and Micronutrients in Parenteral Nutrition for Preterm Newborns: A Narrative Review

Preterm neonates display a high risk of postnatal malnutrition, especially at very low gestational ages, because nutritional stores are less in younger preterm infants. For this reason nutrition and growth in early life play a pivotal role in the establishment of the long-term health of premature infants. Nutritional care for preterm neonates remains a challenge in clinical practice. According to the recent and latest recommendations from ESPGHAN, at birth, water intake of 70–80 mL/kg/day is suggested, progressively increasing to 150 mL/kg/day by the end of the first week of life, along with a calorie intake of 120 kcal/kg/day and a minimum protein intake of 2.5–3 g/kg/day. Regarding glucose intake, an infusion rate of 3–5 mg/kg/min is recommended, but VLBW and ELBW preterm neonates may require up to 12 mg/kg/min. In preterm infants, lipid emulsions can be started immediately after birth at a dosage of 0.5–1 g/kg/day. However, some authors have recently shown that it is not always possible to achieve optimal and recommended nutrition, due to the complexity of the daily management of premature infants, especially if extremely preterm. It would be desirable if multicenter randomized controlled trials were designed to explore the effect of early nutrition and growth on long-term health.     

New perspectives on techniques for the clinical psychiatrist: Brain stimulation,chronobiology and psychiatric brain imaging

This review summarizes a scientific dialogue between representatives in non‐pharmacological treatment options of affective disorders. Among the recently introduced somatic treatments for depression those with most evidenced efficacy will be discussed. The first part of this article presents current opinions about the clinical applications of transcranial magnetic stimulation in the treatment of depression. The second part explains the most relevant uses of chronobiology in mood disorders, while the last part deals with the main perspectives on brain imaging techniques in psychiatry. The aim was to bridge gaps between the research evidence and clinical decisions, and reach an agreement on several key points of chronobiological and brain stimulation techniques, as well as on relevant objectives for future research.     

Short‐ and intermediate‐term efficacy of buprenorphine TDS in chronic painful neuropathies

Abstract Buprenorphine is a potent opioid available as a transdermal delivery system (TDS) formulation. This open‐label study investigated its safety, tolerability, and efficacy in 30 patients with chronic painful neuropathy. Subjects with visual analogue scale (VAS) score ≥5 under stable analgesic treatment were entered. The starting dosage of 35 μg/h was increased up to 70.0 μg/h in case of unsatisfactory pain control as assessed by fortnightly visits. The primary endpoint was the number of patients achieving at least 30% pain relief at day 42 visit. Treatment was safe over the study period. Nine patients dropped out for side effects, mostly nausea and daily sleepiness. Buprenorphine TDS was well tolerated in 21 patients. Thirteen patients achieved >30% of pain relief at day 42 visit. Five patients needed to increase the dosage to 52.5 μg/h. Eight patients did not meet the primary outcome, but none allowed increasing the dosage to 70 μg/h, and four patients withdrew consent to continue the study before day 42 visit because of a ‘fear to become addicted,’ although 40% had obtained VAS reduction. In our study, which needs to be confirmed by a controlled trial, buprenorphine TDS induced clinically meaningful pain relief in about 40% of patients with chronic painful neuropathy, suggesting its use as a third‐line treatment.     

Nodular melanomas: Analysis of the casistic and relationship with thick melanomas and diagnostic delay

The present study aimed to: (i) define thick melanomas related to nodular melanomas and other melanoma subgroups; and (ii) establish diagnostic delay in relation to the biological behavior of these melanomas and prevention programs. Cutaneous primary melanomas were studied. Nodular melanoma (NM), lentigo maligna melanoma (LMM) and superficial spreading melanoma (SSM) were selected. A further category named vertical growth melanoma (VGM) was also utilized. Analysis for sex, age, different values of thickness (1–2 mm, >2 mm; 1–3 mm, >3 mm; >4 mm), delay to diagnosis and patterns of detection were performed in all of the different subtypes. Eighty‐seven patients with melanomas more than 1 mm of Breslow's thickness out of 506 melanoma were collected. Twenty‐six were nodular cases, 39 SSM, five LMM and 17 VGM. Of those patients with NM, 42% had a thickness of more than 1–2 mm, 34% of 2–4 mm, 23% of more than 4 mm; and 54% with 1–3, 46% with more than 3 mm; and 58% with more than 2 mm. Even considering different values of thickness of more than 1 mm, a delay to diagnosis was significantly lower in NM (4.79 months) than in other subgroups. The value of more than 1 mm of Breslow's thickness may be sufficient to consider a melanoma to be thick. The lower diagnostic delay of NM suggests that they represent faster growing lesions probably with a different biological behavior than other melanoma subtypes. VGM should not be confused with NM, having a longer delay and different clinical features compared with the latter. They represent an area of diagnostic carelessness than potentially be improved.     

The effects of the aminobisphosphonate alendronate on thyroid hormone-induced osteopenia in rats

Summary We describe a detailed study of fluoride distribution with age in the human cortical rib bone. Human ribs were obtained from 110 subjects (M:68,F;42) aged 20–93 years. The fluoride distribution from the periosteal to endosteal surfaces of the ribs was determined by sampling each specimen using an abrasive micro-sampling technique, and the samples were analyzed using the fluoride electrode, as described by Weatherell et al. [1]. The concentration of fluoride was highest in the periosteal region, decreased gradually towards the interior of the tissue where the concentration of fluoride tended toward the plateau, and then rose again towards the endosteal surface. Patterns of fluoride distribution changed with age, and the difference between periosteal and endosteal fluoride levels increased with age. Although average fluoride concentrations increased with age in both sexes, there was a significant difference between males and females at the age of about 55 years (P<0.05).     

Chronic duloxetine treatment induces specific changes in the expression of BDNF transcripts and in the subcellular localization of the neurotrophin protein.

There is growing evidence that brain-derived neurotrophic factor (BDNF) can be relevant to mood disorders and that modulation of its biosynthesis following prolonged antidepressant treatment may contribute to neuroplastic changes required for clinical response. In the present study, we investigated the effects of the novel antidepressant duloxetine on BDNF in the rat brain. Duloxetine is a serotonin-norepinephrine reuptake inhibitor that differs from other antidepressants by virtue of its balanced potency on both neurotransmitter systems. We found that chronic, but not acute, treatment with duloxetine produces a robust increase of exon V BDNF mRNA levels in frontal cortex when the animals were killed 1 or 24 h after the last administration. The expression of the neurotrophin was also increased in other cortical subregions, but not in the hippocampus. We also found that the increased expression of BDNF in frontal cortex was mainly sustained by enhanced mRNA levels for exons I and III, whereas the expression of exon IV was reduced. Protein analysis in different subcellular fractions showed that chronic treatment with duloxetine, but not with the prototypical SSRI fluoxetine, reduced mature BDNF in the cytosol, but markedly increased its levels in the crude synaptosomal fraction. Our data suggest that chronic treatment with the novel antidepressant duloxetine not only produces a marked upregulation of BDNF mRNA and protein, but may also affect the subcellular redistribution of the neurotrophin. These changes might improve synaptic plasticity and cognitive function that are defective in depressed subjects.     

Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships.

Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates that Cdc7 inhibition can cause selective tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 small-molecule inhibitors for the treatment of cancers. In this paper, the synthesis and structure-activity relationships of 2-heteroaryl-pyrrolopyridinones, the first potent Cdc7 kinase inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, progress toward a simple scaffold, tailored for Cdc7 inhibition, is reported.