Despite the difficulties inherent in biochemical studies of clinically relevant tissue samples, numerous investigations have illuminated the signal transduction mechanisms in patients with BD. These studies also suggest that BD may be due to the interaction of many abnormalities. In this context, novel techniques enabling the study of gene expression promise to assist in untangling these complex interactions, through visualizing the end result of these changes at the level of gene transcription.

Previous studies have implicated a number of biochemical pathways in the etiology of bipolar disorder (BD). However, the precise abnormalities underlying this disorder remain to be established. To investigate novel factors that may be important in the pathophysiology of BD, we utilized cDNA expression arrays to examine differences in expression of up to 1200 genes known to be involved in potentially relevant biochemical processes. This investigation was undertaken in post-mortem samples of frontal cortex tissue from patients with BD and matched controls, obtained (n 10/group) from the Stanley Foundation Neuropathology Consortium. Results include signi®cant (greater than 35% change in signal intensity) differences between BD and controls in a number of genes (n 24). Selected targets were analyzed by RT-PCR, which con®rmed a decrease in transforming growth factor-beta1 (TGF-b1), and an increase in both caspase-8 precursor (casp-8) and transducer of erbB2 (Tob) expression in BD. We further observed a signi®cant decrease of TGF-b1 mRNA levels in BD by RT-PCR in individual post-mortem samples. Given the neuroprotective role attributed to this inhibitory cytokine, our results suggest that the downregulation of TGF-b1 may lead to various neurotoxic insults potentially involved in the etiology of certain mood disorders. Bipolar disorder (BD) is a common psychiatric illness, with a lifetime prevalence of approximately 1.5% (Goodwin and Jamison 1990;Goodwin and Ghaemi 1998). It is characterized by episodes of mania and depression exhibiting increasing chronicity and severity over time, and requires aggressive long-term prophylactic pharmacotherapy. While the causes of BD remain to be conclusively established, Post and colleagues have suggested that lasting neurobiological changes may arise as a result of episode-speci®c alterations in gene expression patterns (Post 1992;Post and Weiss 1996). More recently, studies have shown that changes in gene expression are critical to the effects of long-term treatment with mood stabilizing drugs (Hyman and Nestler 1996), and the associated biochemical mechanisms may be integral to the pathophysiology of BD.Signal transduction pathways are uniquely positioned for the transmission of extracellular signals to long-term neuroplastic events, given their central role in mediating diverse neurotransmitter functions and integrating neuronal communication in the CNS. A large number of reports have been published suggesting the involvement of signal transduction processes in the pathophysiology of BD, as well as in the action of mood stabilizing drugs (Mork et al. 1992; Lenox 1994, 2000a,b;Wang et al. 1997). Moreover, kindling and apoptosis have also provided useful models for understanding the long-term changes that may be associated with the disorder (Post and Weiss 1989; Post 1992), leading to investigation of these processes in BD. Of relevance, mood stabilizers can provide protection against cell death possibly through regulation of antiapoptotic genes (Nonaka et al. 1998), sugges...

OBJECTIVE The efficacy of endoscopic third ventriculostomy (ETV) for the treatment of pediatric hydrocephalus has been extensively reported in the literature. However, ETV-related long-term outcome data are lacking for the adult hydrocephalus population. The objective of the present study was to assess the role of ETV as a primary or secondary treatment for hydrocephalus in adults. METHODS The authors performed a retrospective chart review of all adult patients (age ≥ 18 years) with symptomatic hydrocephalus treated with ETV in Calgary, Canada, over a span of 20 years (1994–2014). Patients were dichotomized into a primary or secondary ETV cohort based on whether ETV was the initial treatment modality for the hydrocephalus or if other CSF diversion procedures had been previously attempted respectively. Primary outcomes were subjective patient-reported clinical improvement within 12 weeks of surgery and the need for any CSF diversion procedures after the initial ETV during the span of the study. Categorical and actuarial data analysis was done to compare the outcomes of the primary versus secondary ETV cohorts. RESULTS A total of 163 adult patients with symptomatic hydrocephalus treated with ETV were identified and followed over an average of 98.6 months (range 0.1–230.4 months). All patients presented with signs of intracranial hypertension or other neurological symptoms. The primary ETV group consisted of 112 patients, and the secondary ETV consisted of 51 patients who presented with failed ventriculoperitoneal (VP) shunts. After the initial ETV procedure, clinical improvement was reported more frequently by patients in the primary cohort (87%) relative to those in the secondary ETV cohort (65%, p = 0.001). Additionally, patients in the primary ETV group required fewer reoperations (p < 0.001), with cumulative ETV survival time favoring this primary ETV cohort over the course of the follow-up period (p < 0.001). Fifteen patients required repeat ETV, with all but one experiencing successful relief of symptoms. Patients in the secondary ETV cohort also had a higher incidence of complications, with one occurring in 8 patients (16%) compared with 2 in the primary ETV group (2%; p = 0.010), although most complications were minor. CONCLUSIONS ETV is an effective long-term treatment for selected adult patients with hydrocephalus. The overall ETV success rate when it was the primary treatment modality for adult hydrocephalus was approximately 87%, and 99% of patients experience symptomatic improvement after 2 ETVs. Patients in whom VP shunt surgery fails prior to an ETV have a 22% relative risk of ETV failure and an almost eightfold complication rate, although mostly minor, when compared with patients who undergo a primary ETV. Most ETV failures occur within the first 7 months of surgery in patients treated with primary ETV, but the time to failure is more prolonged in patients who present with failed previous shunts.

Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric disorder with a strong genetic component, and may involve autoimmune processes. Support for this latter hypothesis comes from the identification of a subgroup of children, described by the term pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS), with onset of OCD symptoms following streptococcal infections. Genes involved in immune response therefore represent possible candidate genes for OCD, including the myelin oligodendrocyte glycoprotein (MOG) gene, which plays an important role in mediating the complement cascade in the immune system. Four polymorphisms in the MOG gene, a dinucleotide CA repeat (MOG2), a tetranucleotide TAAA repeat (MOG4), and 2 intronic single nucleotide polymorphisms, C1334T and C10991T, were investigated for the possibility of association with OCD using 160 nuclear families with an OCD proband. We examined the transmission of alleles of these four polymorphisms with the transmission disequilibrium test (TDT). A biased transmission of the 459-bp allele (allele 2: chi2 = 5.255, P = 0.022) of MOG4 was detected, while MOG2, C1334T, and C10991T showed no statistically significant bias in the transmission of alleles. The transmission of the C1334T.MOG2.C10991T.MOG4 haplotype 1.13.2.2 (chi2 = 6.426, P = 0.011) was also significant. Quantitative analysis using the family-based association test (FBAT) was significant for MOG4 in total Yale-Brown Obsessive-Compulsive Scale severity score (allele 2: z = 2.334, P = 0.020). Further investigations combining genetic, pathological, and pharmacological strategies, are warranted.

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