Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders.

Prenatal stress is a risk factor for several psychiatric disorders in which inhibitory neuron pathology is implicated. A growing body of research demonstrates that inhibitory circuitry in the brain is directly and persistently affected by prenatal stress. This review synthesizes research that explores how this early developmental risk factor impacts inhibitory neurons and how these findings intersect with research on risk factors and inhibitory neuron pathophysiology in schizophrenia, anxiety, autism and Tourette syndrome. The specific impact of prenatal stress on inhibitory neurons, particularly developmental mechanisms, may elucidate further the pathophysiology of these disorders.

No association of multiple type 2 diabetes loci with type 1 diabetes.

AIMS/HYPOTHESIS: We used recently confirmed type 2 diabetes gene regions to investigate the genetic relationship between type 1 and type 2 diabetes, in an average of 7,606 type 1 diabetic individuals and 8,218 controls, providing >80% power to detect effects as small as an OR of 1.11 at a false-positive rate of 0.003. METHODS: The single nucleotide polymorphisms (SNPs) with the most convincing evidence of association in 12 type 2 diabetes-associated gene regions, PPARG, CDKAL1, HNF1B, WFS1, SLC30A8, CDKN2A-CDKN2B, IGF2BP2, KCNJ11, TCF7L2, FTO, HHEX-IDE and THADA, were analysed in type 1 diabetes cases and controls. PPARG and HHEX-IDE were additionally tested for association in 3,851 type 1 diabetes families. Tests for interaction with HLA class II genotypes, autoantibody status, sex, and age-at-diagnosis of type 1 diabetes were performed with all 12 gene regions. RESULTS: Only PPARG and HHEX-IDE showed any evidence of association with type 1 diabetes cases and controls (p = 0.004 and p = 0.003, respectively; p > 0.05 for other SNPs). The potential association of PPARG was supported by family analyses (p = 0.003; p (combined) = 1.0 x 10(-4)). No SNPs showed evidence of interaction with any covariate (p > 0.05). CONCLUSIONS/INTERPRETATION: We found no convincing genetic link between type 1 and type 2 diabetes. An association of PPARG (rs1801282/Pro12Ala) could be consistent with its known function in inflammation. Hence, our results reinforce evidence suggesting that type 1 diabetes is a disease of the immune system, rather than being due to inherited defects in beta cell function or regeneration or insulin resistance.

CD226 Gly307Ser association with multiple autoimmune diseases.

Genome-wide association studies provide insight into multigenic diseases through the identification of susceptibility genes and etiological pathways. In addition, the identification of shared variants among autoimmune disorders provides insight into common disease pathways. We previously reported an association of a nonsynonymous single nucleotide polymorphism (SNP) rs763361/Gly307Ser in the immune response gene CD226 on chromosome 18q22 with type 1 diabetes (T1D) susceptibility. Here, we report efforts toward identifying the causal variant by exonic resequencing and tag SNP mapping of the 18q22 region in both T1D and multiple sclerosis (MS). In addition to the analysis of newly available samples in T1D (2088 cases and 3289 controls) and autoimmune thyroid disease (AITD) (821 cases and 1920 controls), resulting in strong support for the Ser(307) association with T1D (P=3.46 x 10(-9)) and continued potential evidence for AITD (P=0.0345), we provide evidence for association of Gly307Ser with MS (P=4.20 x 10(-4)) and rheumatoid arthritis (RA) (P=0.017). The Ser(307) allele of rs763361 in exon 7 of CD226 predisposes to T1D, MS, and possibly AITD and RA, and based on the tag SNP analysis, could be the causal variant.

Evaluation of single nucleotide polymorphism typing with invader on PCR amplicons and its automation.

Large-scale pharmacogenetics and complex disease association studies will require typing of thousands of single-nucleotide polymorphisms (SNPs) in thousands of individuals. Such projects would benefit from a genotyping system with accuracy >99% and a failure rate <5% on a simple, reliable, and flexible platform. However, such a system is not yet available for routine laboratory use. We have evaluated a modification of the previously reported Invader SNP-typing chemistry for use in a genotyping laboratory and tested its automation. The Invader technology uses a Flap Endonuclease for allele discrimination and a universal fluorescence resonance energy transfer (FRET) reporter system. Three hundred and eighty-four individuals were genotyped across a panel of 36 SNPs and one insertion/deletion polymorphism with Invader assays using PCR product as template, a total of 14,208 genotypes. An average failure rate of 2.3% was recorded, mostly associated with PCR failure, and the typing was 99.2% accurate when compared with genotypes generated with established techniques. An average signal-to-noise ratio (9:1) was obtained. The high degree of discrimination for single base changes, coupled with homogeneous format, has allowed us to deploy liquid handling robots in a 384-well microtitre plate format and an automated end-point capture of fluorescent signal. Simple semiautomated data interpretation allows the generation of approximately 25,000 genotypes per person per week, which is 10-fold greater than gel-based SNP typing and microsatellite typing in our laboratory. Savings on labor costs are considerable. We conclude that Invader chemistry using PCR products as template represents a useful technology for typing large numbers of SNPs rapidly and efficiently.

Ensemble responses of the auditory nerve to normal and whispered stop consonants.

Whispered syllables lack many of the frequency and voicing cues of normally voiced speech, but these two acoustically distinct forms of speech are placed into the same linguistic categories. To examine how whispered and voiced speech are encoded in the auditory system, the responses to speech sounds were recorded from 132 single auditory nerve fibers in 20 ketamine anesthetized chinchillas. Stimuli were the naturally produced syllables /da/ and /ta/ presented in whispered and normal voicing. The results for each syllable presented at a fixed intensity were analyzed by pooling the responses from individual auditory nerve fibers across animals to create a global average peri-stimulus time (GAPST) histogram. For each word-initial consonant, the pattern of peaks in the GAPST was the same for both normal and whispered speech. For the vowel the GAPSTs for the whispered speech sounds did not display the synchronization observed in the responses to the voiced syllables. The temporal pattern of the peaks was constant over a 40 dB intensity range, although peak sizes varied. Grouping fibers within different frequency ranges created local averages (LAPST) that revealed the significant contribution of high frequency fibers in the response to the whispered consonants. Responses of individual fibers varied with both the syllable and the voicing. These findings suggest that the encoding of either a whispered or a normal stop consonant results in the same temporal pattern in the ensemble response.

Responses of auditory nerve fibers to trains of clicks.

Responses of auditory nerve fibers to trains of clicks were recorded in ketamine anesthetized chinchillas. By varying the number of clicks and the interclick interval, this study examined whether "post-onset adaptation," described in psychoacoustic experiments on localization, occurred in auditory nerve fibers. The results showed that the number of action potentials recorded from a nerve fiber in response to a train of clicks was a power function of the number of clicks. For interclick intervals of 2 ms or greater the exponent of the power function was 0.5, and this exponent did not change over a 20-dB range of intensities. The timing of action potentials relative to the click stimuli was measured using synchronization coefficients. The coefficients increased with interclick interval, decreased with increasing intensity, and were greater for fibers with low rates of spontaneous activity than for high spontaneous fibers. Recovery functions showed that for interclick intervals of 2 ms or more, the responses to the second click were at least 70% of the response to the initial click. The recovery depended upon the number of clicks in the train. These findings indicate that auditory nerve fibers respond to high rates of stimulus presentation and do not display the adaptation observed in localization studies.

Efficacy of nuclear scintigraphy in the diagnosis and management of sinusitis.

OBJECTIVE: The purpose of this study was to determine whether or not nuclear scintigraphy is useful in the diagnosis and management of chronic sinusitis. The ideal isotope(s) and drawbacks of the different isotopes in different clinical situations are reviewed and discussed. DESIGN: A retrospective review of patients undergoing nuclear medicine studies to aid in the diagnosis and management of sinus disease was carried out. METHOD: Ideal candidates were chosen from both previously operated and unoperated patients whose computed tomography (CT) scan findings could not differentiate benign mucosal thickening from active inflammation. Nuclear scintigraphy scans using indium (In-111), gallium (Ga-67), and technetium (Tch-99m) were used to differentiate acute infection from chronic inflammation involving bone (osteitis) and/or mucosa. This information was then used to guide the management of their condition. Nuclear scintigraphy results were compared to findings on CT scan and during surgery. RESULTS: In-111 was found to be the best isotope for identifying pus or acute disease in the sinuses whereas Ga-67 was very good for identifying both chronic mucosal disease as well as acute disease. Tch-99m was very sensitive for identifying bony remodelling and was therefore not found to be useful if the patient had undergone previous sinus surgery. CONCLUSION: Although not to be considered, in our view, a first-line diagnostic test, nuclear scintigraphy, is useful in cases where CT results are nondifferentiating.

The efficacy of nasal septal surgery.

Nasal septal deformity is a frequent clinical entity, and septoplasty comprises one of the most common procedures performed by otolaryngologists today. Its efficacy seems intuitive, however the literature reveals relatively few papers confirming its utility. In this study, all patients undergoing septal reconstruction (excluding septorhinoplasty) at three major teaching hospitals in Vancouver during the years 1988 to 1990 were reviewed retrospectively in a two-pronged study. Information was collected concerning symptoms, physical findings and surgical technique. In the second phase, patients were contacted by telephone in a blinded fashion. Data was collected concerning patient satisfaction regarding various parameters including initial and ultimate symptom resolution, acceptance of nasal packing and postoperative complications. The following conclusions may be drawn: 1) Septoplasty was successful in relieving nasal obstruction in 70.5% of patients. 2) Turbinate surgery including outfracturing appears to significantly improve the outcome of surgery. 3) Rhinitis, including allergy, congestion, postnasal drip and rhinorrhea did not significantly affect success in relieving nasal obstruction. 4) Nasal packing did not significantly affect the outcome, but was the most frequently complained of aspect of the surgery. Therefore, we do not feel nasal packing is necessary.

Allergic and inflammatory aspects of chronic rhinosinusitis.

The pathophysiology of rhinosinusitis is complex and poorly understood. Although it is recognized that obstruction of the sinus ostia which is surgically correctable contributes to recurrent bacterial sinusitis, allergic and nonallergic inflammation may contribute to or mimic infectious rhinosinusitis. Those aspects of rhinosinusitis which are not necessarily surgically correctable require consideration and may affect surgical prognosis. This article focuses on those considerations.

Vascular complication of neck space infection: case report and literature review.

Antibiotic therapy has changed the face of medicine radically, and physicians no longer have the empirical knowledge of bacterial infections that they once had. Consequently, the diagnosis and management of complicated infections presents a significant challenge to today's otolaryngologists. We present a rare complication, even before the advent of antibiotics, of a head and neck infection: a carotid artery pseudoaneurysm resulting from peritonsillar abscess. The diagnosis and management of this problem is discussed and the pertinent literature reviewed.

Epistaxis.

Good equipment, readily available, and organized management are essential for successful control of epistaxis without exacerbating the patient's trauma. Epistaxis most commonly results from localized causes but can reflect systemic disease. The author describes practical management of epistaxis, particularly for acute problems in the emergency room.

Intranasal sphenoethmoidectomy: 10-year experience and literature review.

We believe that complete intranasal sphenoethmoidectomy is the procedure of choice for massive nasal polyposis and polypoid sinusitis. The anatomy is complex, visualization with conventional matters is limited, and the potential complications can be severe. Nevertheless, with thorough underlying knowledge of the anatomy and proper training consisting of cadaver dissection and supervised surgery, a safe, effective technique can be mastered. Two hundred and thirty sphenoethmoidectomies done in 87 patients over the past 10 years are reviewed. The initial recurrence rate was 25%. There was a 3% incidence of serious complications. These results are comparable to those in the literature. While recognizing the potential complications of this difficult procedure, we believe that it can be performed safely and effectively by properly trained surgeons and that an effort should be made to extend proper instruction to otolaryngology residents.

Bilateral gustatory rhinorrhea following bilateral parotidectomy: a case report.

To the authors' knowledge, no cases of gustatory rhinorrhea following parotidectomy have been reported. A case is presented of a 28-year-old woman who underwent bilateral parotidectomies within a four-year period for congenital sialectasia and secondary infection. Both operations were complicated by Frey's syndrome and she also developed bilateral gustatory rhinorrhea. The successful management of this problem with bilateral vidian neurectomies and the refractory nature of her Frey's syndrome, finally controlled with tympanic neurectomies, are discussed.