Linkage of bipolar disorder to chromosome 18q and the validity of bipolar II disorder.

BACKGROUND: An analysis of the relationship between clinical features and allele sharing could clarify the issue of genetic linkage between bipolar affective disorder (BPAD) and chromosome 18q, contributing to the definition of genetically valid clinical subtypes. METHODS: Relatives ascertained through a proband who had bipolar I disorder (BPI) were interviewed by a psychiatrist, assigned an all-sources diagnosis, and genotyped with 32 markers on 18q21-23. Exploratory findings from the first 28 families (n = 247) were tested prospectively in an additional 30 families (n = 259), and the effect of confirmed findings on the linkage evidence was assessed. RESULTS: In exploratory analyses, paternal allele sharing on 18q21 was significantly (P =.03) associated with a diagnostic subtype, and was greatest in pairs where both siblings had bipolar II disorder (BPII). Prospective analysis confirmed the finding that BPII-BPII sibling pairs showed significantly (P =.016) greater paternal allele sharing. Paternal allele sharing across 18q21-23 was also significantly greater in families with at least one BPII-BPII sibling pair. In these families, multipoint affected sibling-pair linkage analysis produced a peak paternal lod score of 4.67 (1-lod confidence interval, 12 centimorgans [cM]) vs 1.53 (1-lod confidence interval, 44 cM) in all families. CONCLUSIONS: Affected sibling pairs with BPII discriminated between families who showed evidence of linkage to 18q, and families who did not. Families with a BPII sibling pair produced an increased lod score and improved linkage resolution. These findings, limited by the small number of BPII-BPII sibling pairs, strengthen the evidence of genetic linkage between BPAD and chromosome 18q, and provide preliminary support for BPII as a genetically valid subtype of BPAD.     

Evaluation of the response to a booster dose of hepatitis B vaccine in previously immunized healthcare workers.

INTRODUCTION: Hepatitis B vaccination is recommended for all healthcare workers (HCW) at risk of exposure to infectious body fluids. However, the absolute duration of protection from immunization is unknown. The purpose of this randomized comparison trial was to determine how previously immunized HCW respond to different booster doses of hepatitis B vaccine. METHOD: Adult HCW (n=59) were classified by level of hepatitis B surface antigen (anti-HBs), either <10 milli-International Units per milliliter (mIU/ml) or 10-50 mIU/ml. Participants were then randomized to receive a 2.5 or 10 microg dose of hepatitis B vaccine. Evaluation of anti-HBs levels were conducted 10 to 14 days, one month and one year postbooster. RESULTS AND DISCUSSION: All participants responded to the booster dose with increased anti-HBs levels. At 14 days, mean anti-HBs levels were significantly higher for those with higher levels at baseline (P=0.004) and those receiving the 10 microg dose (P=0.016). At one month, those with higher anti-HBs levels at baseline and those receiving the 10 microg dose were significantly higher (P<0.01 for both). At one year, the increase for the higher dose was no longer statistically significant when examined by itself (P=0.081); statistical significance (P=0.021) was achieved after adjusting for anti-HBs level at baseline. For all participants, the geometric mean anti-HBs level was 2618 mIU/ml at 14 days, 2175 mIU/ml at one month and 88.9 mIU/ml at one year. At all time points the increase in anti-HBs levels represented an increase over the geometric mean baseline level of anti-HBs (7.4 mIU/ml). Hepatitis B immunized adults responded to a booster dose of hepatitis B vaccine from 3 to 13 yr postvaccination series. Data support current recommendations that immunized HCW do not require periodic antibody testing or vaccine boosters.     

Hypersensitivity reactions associated with exposure to naproxen and ibuprofen: A cohort study

The aim of the study was to evaluate the risks of hospitalisation and death due to hypersensitivity reactions associated with the NSAIDs naproxen and ibuprofen, using a record-linkage database for Tayside, Scotland (population 400,000). Cohorts of patients exposed to naproxen (n=54,038) and ibuprofen (n=79,513) were assembled. There were no deaths due to hypersensitivity. There was an increased risk of unvalidated hypersensitivity reactions during periods on-drug versus off-drug in patients exposed to naproxen and ibuprofen. However, after checking medical records, none of the three valid cases of hypersensitivity in the naproxen cohort and neither of the two in the ibuprofen cohort were judged to be due to NSAID exposure. A ‘worst-case’ scenario gave an adjusted rate-ratio of on-drug with naproxen versus on-drug with ibuprofen of 1.63 (0.50, 5.29). The study shows that hypersensitivity reactions associated with NSAID use are rare, and provides no evidence that the risks of hypersensitivity reactions differ between naproxen and ibuprofen.     

Patient-reported quality of life after salvage brachytherapy for radio-recurrent prostate cancer: A prospective Phase II study

BackgroundPatient-reported quality of life (QOL) after salvage brachytherapy for radiorecurrent prostate cancer has not been well-characterized prospectively.MethodsWe examined 25 men who recurred after primary radiotherapy for prostate cancer and received MRI-guided salvage brachytherapy as part of a prospective Phase II study. These patients received prospectively a validated patient-reported QOL questionnaire to fill out at baseline, as well as 3, 15, and 27 months after re-irradiation to determine the degree of sexual, bowel, and urinary dysfunction (maximum dysfunction score = 100).ResultsOn average, sexual function continued to decline with time, and patients had significantly worse sexual function scores at 27 months than baseline (p = 0.01). Although bowel and urinary symptoms worsened acutely at 3 or 15 months, they showed on average some improvement by 27 months, and there were no significant differences between baseline and 27-month urinary or bowel scores. An interval to re-irradiation less than 4.5 years and prior brachytherapy were each associated significantly with the largest decrements in bowel function (p = 0.035).ConclusionSimilar to the patterns seen in the de novo setting, patients who receive salvage brachytherapy report a worsening of bowel and urinary symptoms followed by some improvement by 27 months, while sexual function steadily declines over time. Interval to re-irradiation and type of prior radiation received may be used to counsel and optimize selection of men for salvage brachytherapy with regard to QOL endpoints.     

Tumor volume changes on 1.5 tesla endorectal MRI during neoadjuvant androgen suppression therapy for higher-risk prostate cancer and recurrence in men treated using radiation therapy results of the phase II CALGB 9682 study

PURPOSE: We prospectively determined whether the change in tumor volume (TV) during 2 months of neoadjuvant androgen suppression therapy (nAST) measured using conventional 1.5 Tesla endorectal magnetic resonance imaging (eMRI) was associated with the risk of recurrence after radiation (RT) and 6 months of AST. PATIENTS AND METHODS: Between 1997 and 2001, 180 men with clinical stage T1c-T3cN0M0 adenocarcinoma of the prostate were registered. Fifteen were found to be ineligible and the institutional MR radiologist could not assess the TV in 32, leaving 133 for analysis. Multivariable Cox regression analysis was used to assess whether a significant association existed between eMRI-defined TV progression during nAST and time to recurrence adjusting for prostate-specific antigen (PSA) level, Gleason score (8 to 10 or 7 vs. 6 or less) and stage (T3 vs. T1-2). RESULTS: After a median follow up of 6.7 years and adjusting for known prognostic factors, there was a significant increase in the risk of PSA failure (HR, 2.3 [95% CI, 1.1-4.5; p = 0.025) in men with eMRI-defined TV progression during nAST. Specifically, adjusted estimates of PSA failure were significantly higher (p = 0.032) in men with, compared with men without, eMRI-defined TV progression reaching 38% vs. 19%, respectively, by 5 years. CONCLUSION: Eradicating intraprostatic hormone refractory prostate cancer (HRPC) by maximizing local control and randomized trials assessing whether survival is improved when agents active against HRPC are combined with maximal local therapy are needed in men who progress based on eMRI during nAST.     

The use of cortical auditory evoked potentials to evaluate neural encoding of speech sounds in adults

There has been considerable recent interest in the use of cortical auditory evoked potentials (CAEPs) as an electrophysiological measure of human speech encoding in individuals with normal as well as impaired auditory systems. The development of such electrophysiological measures such as CAEPs is important because they can be used to evaluate the benefits of hearing aids and cochlear implants in infants, young children, and adults that cannot cooperate for behavioral speech discrimination testing. The current study determined whether CAEPs produced by seven different speech sounds, which together cover a broad range of frequencies across the speech spectrum, could be differentiated from each other based on response latency and amplitude measures. CAEPs were recorded from ten adults with normal hearing in response to speech stimuli presented at a conversational level (65 dB SPL) via a loudspeaker. Cortical responses were reliably elicited by each of the speech sounds in all participants. CAEPs produced by speech sounds dominated by high-frequency energy were significantly different in amplitude from CAEPs produced by sounds dominated by lower-frequency energy. Significant effects of stimulus duration were also observed, with shorter duration stimuli producing larger amplitudes and earlier latencies than longer duration stimuli. This research demonstrates that CAEPs can be reliably evoked by sounds that encompass the entire speech frequency range. Further, CAEP latencies and amplitudes may provide an objective indication that spectrally different speech sounds are encoded differently at the cortical level.     

Constant light disrupts the developing mouse biological clock

The central biological clock of the brain, contained within the suprachiasmatic nuclei (SCN) of mammals, orchestrates an orderly "internal day" of physiology and behavior. The developing biological clock begins to respond to light at an early stage and a particular concern in humans is whether light exposure has disruptive effects on the developing biological clock of infants exposed to constant lighting conditions in neonatal intensive care units (NICUs). Worldwide, eighteen million, or 14%, of newborns estimated to be of low birth weight, are exposed to artificial lighting environments in hospital nurseries annually. Here, we have tested whether constant light (LL) exposure disrupts the developing biological clock of mice, using a circadian reporter transgenic mouse model in which the organization of the central biological clock can be assayed by real-time gene expression imaging. We now find that LL has both acute and long-term disruptive effects on developing biological clocks and that cyclic lighting conditions are critical for developing circadian clocks to coordinate their molecular circadian mechanisms. This suggests that, from the perspective of developing circadian organization in humans, cyclic light conditions in NICUs are likely to be most appropriate for infants.     

Mice lacking acid‐sensing ion channels (ASIC) 1 or 2, but not ASIC3, show increased pain behaviour in the formalin test

Extracellular acidification is a component of the inflammatory process and may be a factor driving the pain accompanying it. Acid-sensing ion channels (ASICs) are neuronal proton sensors and evidence suggests they are involved in signalling inflammatory pain. The aims of this study were to (1) clarify the role of ASICs in nociception and (2) confirm their involvement in inflammatory pain and determine whether this was subunit specific.This was achieved by (1) direct comparison of the sensitivity of ASIC1, ASIC2, ASIC3 and TRPV1 knockout mice versus wildtype littermates to acute thermal and mechanical noxious stimuli and (2) studying the behavioural responses of each transgenic strain to hind paw inflammation with either complete Freund’s adjuvant (CFA) or formalin.Naïve ASIC1^?/? and ASIC2^?/? mice responded normally to acute noxious stimuli, whereas ASIC3^?/? mice were hypersensitive to high intensity thermal stimuli. CFA injection decreased mechanical and thermal withdrawal thresholds for up to 8 days. ASIC2^?/? mice had increased mechanical sensitivity on day 1 post-CFA compared to wildtype controls. TRPV1^?/? mice had significantly reduced thermal, but not mechanical, hyperalgesia on all days after inflammation. Following formalin injection, ASIC1^?/? and ASIC2^?/?, but not ASIC3^?/? or TRPV1^?/?, mice showed enhanced pain behaviour, predominantly in the second phase of the test.These data suggest that whilst ASICs may play a role in mediating inflammatory pain, this role is likely to be modulatory and strongly dependent on channel subtype.     

CCL2 is a key mediator of microglia activation in neuropathic pain states

While neuroimmune interactions are increasingly recognized as important in nociceptive processing, the nature and functional significance of these interactions is not well defined. There are multiple reports that the activation of spinal microglia is a critical event in the generation of neuropathic pain behaviors but the mediators of this activation remain disputed. Here we show that the chemokine CCL2, produced by both damaged and undamaged primary sensory neurons in neuropathic pain states in rats, is released in an activity dependent manner from the central terminals of these fibres. We also demonstrate that intraspinal CCL2 in naïve rats leads to activation of spinal microglia and neuropathic pain‐like behavior. An essential role for spinal CCL2 is demonstrated by the inhibition of neuropathic pain behavior and microglial activation by a specific neutralising antibody to CCL2 administered intrathecally. Thus, the neuronal expression of CCL2 provides a mechanism for immune activation, which in turn regulates the sensitivity of pain signaling systems in neuropathic pain states.