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Buprenorphine and naloxone (Suboxone) is a combination medication-assisted treatment (MAT) for opioid use disorder. MAT withdrawal-induced psychosis is a rare clinical presentation. To our best knowledge, only three reports have summarized the characteristic manifestations of buprenorphine withdrawal psychosis, yet all of them were male. In this case report, we present a 41-year-old female patient with bipolar disorder and comorbid substance use disorder who developed new-onset psychosis and relapse of manic symptoms following abrupt discontinuation of Suboxone. Manic and psychotic symptoms remitted after a short-term hospitalization with the treatment of an antipsychotic and a mood stabilizer. In addition to discussing this case presentation and treatment approach, we review existing literature and discuss possible underlying mechanisms to enhance understanding of this clinical phenomenon. Psychopharmacology Bulletin. Accepted version

TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.

Background According to experimental and clinical published studies, patients with keratoconus have a genetic predisposition to corneal ectasia; however, ectasia might not be activated or reactivated unless an additional stressful event triggers the disease. Triggering factors are sources of reactive oxidative stress; among them, mechanical trauma (vigorous eye rubbing, poorly fit contact lenses), exposure to ultraviolet light, and atopy/allergies. The aim of this case report is to present for the first time a case of rapidly progressive corneal ectasia in a patient with keratoconus following uncomplicated phacoemulsification surgery for cataract removal. Case presentation A 38-year-old Caucasian man was referred to our out-patient’s service due to bilateral cataract. He also had bilateral keratoconus and had undergone corneal cross-linking in both his eyes 5 years prior to his referral. Ever since the corneal cross-linking, keratoconus had been stable. He underwent a full ophthalmological examination including slit-lamp biomicroscopy, optical biometry, Scheimpflug tomography, corneal biomechanical assessment, and fundus examination. He presented advanced centrally located cataract with count fingers for preoperative best-corrected visual acuity. An uncomplicated cataract extraction surgery was performed. Preoperative flat keratometry reading was 40.5 diopters, steep keratometry reading was 41.8 diopters, astigmatism was 1.3 diopters, corneal hysteresis was 8.2, corneal resistance factor was 7.5, and thinnest corneal thickness was 503 μm. Within 3 months, he demonstrated rapidly progressing corneal ectasia in his operated eye, while 6 months postoperatively, flat keratometry reading was 45.5 diopters, steep keratometry reading was 48.3 diopters, astigmatism was 2.8 diopters, corneal hysteresis = 6.8, corneal resistance factor = 7.5, and thinnest corneal thickness = 318 μm. Conclusions To the best of our knowledge, this is the first report to describe corneal ectasia in a patient with keratoconus following phacoemulsification surgery. Cataract surgeons should provide extra caution to patients with keratoconus and take into consideration this rare but potentially sight-threatening complication.

On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two‐hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor‐predisposing syndromes. To understand the molecular mechanism of two‐hit‐initiated tumorigenesis, Knudson used an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor‐predisposing syndrome. Animal models, including the fly, have greatly contributed to TSC research. Because the product of the TSC2/Tsc2 gene (tuberin) together with hamartin, the product of another TSC gene (TSC1/Tsc1), suppresses mammalian/mechanistic target of rapamycin complex 1 (mTORC1), rapalogs have been used as therapeutic drugs for TSC. Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are mTORC1‐independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with TSC2/Tsc2 gene mutations, will facilitate the understanding of new aspects of TSC pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of TSC and introduce recent progress in TSC research.

Neonatal seizures have been associated with the later development of postneonatal epilepsy, mainly beginning within the first year of life. Mechanisms of epileptogenesis in the immature brain still need to be fully elucidated but a two-hit hypothesis, showing that an early insult heightens later susceptibility to seizure-induced brain damage, has been demonstrated in animal models. We describe 2 cases of preterm babies sustaining recurrent neonatal seizures in the context of a severe perinatal brain damage who presented with symptomatic epilepsy only after the occurrence of an episode of febrile status epilepticus. In the context of preexisting perinatal brain damage, febrile status epilepticus acted as a second hit for developing epilepsy, confirming animal evidence.

Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

This paper integrates the cumulative stress hypothesis with the mismatch hypothesis, taking into account individual differences in sensitivity to programming. According to the cumulative stress hypothesis, individuals are more likely to suffer from disease as adversity accumulates. According to the mismatch hypothesis, individuals are more likely to suffer from disease if a mismatch occurs between the early programming environment and the later adult environment. These seemingly contradicting hypotheses are integrated into a new model proposing that the cumulative stress hypothesis applies to individuals who were not or only to a small extent programmed by their early environment, while the mismatch hypothesis applies to individuals who experienced strong programming effects. Evidence for the main effects of adversity as well as evidence for the interaction between adversity in early and later life is presented from human observational studies and animal models. Next, convincing evidence for individual differences in sensitivity to programming is presented. We extensively discuss how our integrated model can be tested empirically in animal models and human studies, inviting researchers to test this model. Furthermore, this integrated model should tempt clinicians and other intervenors to interpret symptoms as possible adaptations from an evolutionary biology perspective. (C) 2011 Elsevier Inc. All rights reserved.