Implications of comorbidity for genetic studies of bipolar disorder: P300 and eye tracking as biological markers for illness

In large families with affective illness, identification of a biological variable is needed that reflects brain dysfunction at an earlier point than symptom development. Eye movement disorder, a possible vulnerability marker in schizophrenia, is less clearly associated with affective illness, although a subgroup of affective disorders shows smooth-pursuit eye movement disorder. The auditory P300 event-related potential may be a useful marker for risk to schizophrenia, but a role in bipolar illness is less certain. The distribution of these two biological variables and their association with symptoms in two multiply affected bipolar families is described. In a single, five-generation family identified for linkage studies through two bipolar I (BPI) probands, 128 members (including 20 spouses) were interviewed. The 108 related individuals had diagnoses of BPI (7), bipolar II (2), cyclothymia (3), or major depressive disorder (19). Eight others had generalised anxiety (1), minor depression (5), intermittent depression (1), or alcoholism (1). Sixty-nine subjects had no psychiatric diagnosis. P300 latency (81) and eye tracking (71) were recorded from a subgroup of relatives within the pedigree. Eye tracking was abnormal in 11 of 71 relatives (15.5%) and was bimodally distributed. In these 11 relatives, clinical diagnoses included minor depression (1), alcoholism (1) and generalised anxiety disorder (1). P300 latency was normally distributed and did not differ from controls. In a second family in which five of seven siblings have BPI illness, P300 latency and eye movement disorder were found in affected relatives and in some unaffected offspring. In these large families, clinical diagnoses of general anxiety, alcoholism and minor depression, when associated with eye tracking abnormality, may be considered alternative clinical manifestations of the same trait that in other relatives is expressed as bipolar illness.     

Electrophysiologic characteristics and anatomical complexities of accessory atrioventricular pathways with successful ablation of anterograde and retrograde conduction at different sites

INTRODUCTION: Catheter ablation may eliminate anterograde and retrograde accessory pathway conduction at closely adjacent but anatomically discrete sites. However, the mechanisms of this discrepancy, the electrophysiologic and anatomical characteristics, and information about systematic study from a large patient population are not available. The purpose of this study was to investigate the electrophysiologic characteristics and anatomical complexities of the accessory pathway in which anterograde and retrograde conduction was successfully ablated at different sites. METHODS AND RESULTS: Thirty-eight (10.9%) patients (19 men and 19 women; mean age 37 +/- 2.4 years) fulfilling the criteria of having separate ablation sites for anterograde and retrograde conduction were designated as group I, and the other 310 patients (215 men and 95 women; mean age 47 +/- 0.6 years) were designated as group II. The patients with right-sided free-wall pathways had the highest incidence (18.6%) of separate ablation sites. The anatomical distance between anterograde and retrograde directions (left anterior oblique view, 13 +/- 0.6 vs 8 +/- 0.9 mm, P < 0.01; right anterior oblique view, 17 +/- 0.6 vs 5 +/- 0.7 mm, P < 0.01), and incidence of conduction impairment in one direction after successful ablation of another direction (15% vs 78%, P < 0.05) differed significantly between left and right free-wall pathways. The mean distances obtained from left (7 +/- 0.4 vs 14 +/- 0.4 mm, P < 0.05) and right (7 +/- 1.1 vs 15 +/- 0.9 mm, P < 0.05) anterior oblique views were shorter in patients who had impairment of conduction properties than those in patients without impaired conduction after successful ablation of one direction. CONCLUSIONS: This study showed that anatomical and functional dissociation of the accessory pathway into anterograde and retrograde components was possible. Further study on the relation between electrophysiologic and pathologic characteristics would be helpful to confirm these findings.     

Elder abuse: a call to action

An estimated 2 million people a year are victims of elder abuse, which ranges from neglect and mistreatment to physical abuse. By the year 2020, a full 22% of the population will be aged 65 or older. This demographic explosion demands that we identify and protect those at risk. To investigate the incidence of elder abuse or neglect (EAN) and to determine clinician awareness of associated risk factors, we conducted a 1-year retrospective review of thermally injured patients aged 60 or older. Data included age, total body surface area burned, mechanism of injury, length of hospital stay, mortality, abuse or neglect risk factors, and referral to the appropriate social agency. We found that our elderly patients (n = 28) were poorly screened for EAN. While 64% to 96% of patients were screened for cognitive impairment, overall health, and financial resources, none were screened for risk factors of emotional isolation. None of the patient's caregivers, including any spouses, roommates, or guardians, were screened for risk factors of substance abuse, familial violence, dependency needs, or external stresses. With the use of available data, we were able to place 11 patients on the following levels of abuse or neglect: 1) low risk for abuse; 2) self-neglect; 3) neglect; and 4) abuse. By this scale, 7 patients (64%) were victims of self-neglect, 3 patients (27%) were victims of neglect, and 1 patient (9%) was a victim of abuse. Adult Protective Services intervened in 2 cases. Recognizing that all cases of EAN should be preventable, we cannot accept the socioeconomic impact of this entity. The 11 patients identified as victims of neglect, self-neglect, or abuse accounted for 135 hospital days and 8 fatalities. Before we can address EAN, health care personnel must be made aware of the problem and routine screening for risk factors must be implemented. The true incidence of EAN is likely underestimated because health care providers have difficulty recognizing its features. A standard assessment tool to screen for neglect or abuse should be used for each older adult admission.     

Evaluation of local anesthesia techniques for small incision cataract surgery

PURPOSE: To evaluate the surgical experiences and patient preference with 3 local anesthesia techniques for small incision cataract surgery. SETTING: Department of Ophthalmology, Hj?rring Hospital, Denmark. METHODS: This prospective, randomized study included 66 patients having simultaneous bilateral cataract surgery. There were 3 test groups, each containing 2 of the following local anesthesia techniques: retro/peribulbar (RBA), sub-Tenon's (STA), or topical (TA). Each patient served as his or her own control. No medical sedation was used. Patient response to each anesthesia technique was evaluated by the surgeon based on surgical difficulties, a nurse using hand-holding tension and verbal interaction, and a visual analog pain score. Patients were also asked which of the 2 techniques they preferred and their reasons. RESULTS: No local anesthesia techniques interfered with surgery. The order of a positive pain/discomfort response during surgery was TA > STA > RBA. Significantly more pain occurred with application of RBA than with STA or TA. No postoperative pain was recorded with any method. Fifty-six percent of patients said they preferred 1 technique over the other; 16% of patients having STA would not do so again, 19% would not have TA again, and 40% would not have RBA again. The main reasons for preferring STA and TA were fear of or pain from a retrobulbar injection. The main reasons for preferring RBA were less awareness, anxiety, and surgical pain. Immediate visual recovery seemed to be of minor importance in patients' choice of an anesthesia technique. CONCLUSION: Although less discomfort/pain occurred during surgery with RBA, patients preferred STA and TA primarily because of the inconvenience or pain of the retrobulbar injection. Although medical sedation was not used in this study, the pain/discomfort ratio from surgery was not greater than in studies using intravenous sedation, indicating that the use of medical sedation should be re-evaluated.     

The 5-HT1A receptor antagonist p-MPPI blocks 5-HT1A autoreceptors and increases dorsal raphe unit activity in awake cats

The effects of the putative 5-HT1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzam ide (p-MPPI) were examined on the activity of serotonergic dorsal raphe nucleus neurons in freely moving cats. Systemic administration of p-MPPI produced a dose-dependent increase in firing rate. This stimulatory effect of p-MPPI was evident during wakefulness (when serotonergic neurons display a relatively high level of activity), but not during sleep (when serotonergic neurons display little or no spontaneous activity). p-MPPI also blocked the ability of the 5-HT1A receptor agonist 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH-DPAT) to inhibit serotonergic neuronal activity. This antagonism was evident both as a reversal of the neuronal inhibition produced by prior injection of 8-OH-DPAT and as a shift in the potency of 8-OH-DPAT following p-MPPI pretreatment. Overall, these results in behaving animals indicate that p-MPPI acts as an effective 5-HT1A autoreceptor antagonist. The increase in firing rate produced by p-MPPI supports the hypothesis that autoreceptor-mediated feedback inhibition operates under physiological conditions.     

Histidine77, glutamic acid81, glutamic acid123, threonine126, asparagine194, and tryptophan197 of the human emopamil binding protein are required for in vivo sterol delta 8-delta 7 isomerization

The human emopamil binding protein (hEBP) exhibits sterol Delta8-Delta7 isomerase activity (EC 5.3.3.5) upon heterologous expression in a sterol Delta8-Delta7 isomerization-deficient erg2-3 yeast strain. Ala scanning mutagenesis was used to identify residues in the four putative transmembrane alpha-helices of hEBP that are required for catalytic activity. Isomerization was assayed in vivo by spectrophotometric quantification of Delta5,7-sterols. Out of 64 Ala mutants of hEBP only H77A-, E81A-, E123A-, T126A-, N194A-, and W197A-expressing yeast strains contained 10% or less of wild-type (wt) Delta5,7-sterols. All substitutions of these six residues with functionally or structurally similar amino acid residues failed to fully restore catalytic activity. Mutants E81D, T126S, N194Q, and W197F, but not H77N and E123D, still bound the enzyme inhibitor 3H-ifenprodil. Changed equilibrium and kinetic binding properties of the mutant enzymes confirmed our previous suggestion that residues required for catalytic activity are also involved in inhibitor binding [Moebius et al. (1996) Biochemistry 35, 16871-16878]. His77, Glu81, Glu123, Thr126, Asn194, and Trp197 are localized in the cytoplasmic halves of the transmembrane segments 2-4 and are proposed to line the catalytic cleft. Ala mutants of Trp102, Tyr105, Asp109, Arg111, and Tyr112 in a conserved cytoplasmic domain (WKEYXKGDSRY) between transmembrane segments 2 and 3 contained less than 10% of wt Delta5,7-sterols, implying that this region also could be functionally important. The in vivo complementation of enzyme-deficient yeast strains with mutated cDNAs is a simple and sensitive method to rapidly analyze the functional consequences of mutations in sterol modifying enzymes.     

The bacterial SecY/E translocation complex forms channel-like structures similar to those of the eukaryotic Sec61p complex

The SecYEG complex is a major component of the protein translocation apparatus in the cytoplasmic membrane of bacteria. We have purified a translocationally active complex of the two subunits, SecY and SecE, from Bacillus subtilis. As demonstrated by electron microscopy, SecY/E forms ring structures in detergent solution and in intact lipid bilayers, often with a quasi-pentagonal appearance in projection. The particles represent oligomeric assemblies of the SecY/E complex and are similar to those formed by the eukaryotic Sec61p complex. We propose that these SecY/E rings represent protein-conducting channels and that the two essential membrane components SecY and SecE are sufficient for their formation.     

Anoxia/reoxygenation-induced tolerance with respect to polymorphonuclear leukocyte adhesion to cultured endothelial cells. A nuclear factor-kappaB-mediated phenomenon

The best available evidence of inhibitory conditioning in vertebrates comes from experiments in which variants of A+/AB- and A+/B- training were compared in terms of response to B in summation and retardation tests, the results suggesting that inhibition is generated by nonreinforcement as an increasing function of the excitatory value of the setting. We report here 7 experiments with foraging honeybees (Apis mellifera) that failed to show a difference in the effects of the 2 treatments. On the basis of previous experiments as well as supplementary experiments whose results give no reason to doubt the sensitivity of the training techniques and measures used, our consistently negative results may mean either that inhibition in honeybees is generated by nonreinforcement independently of the setting or that there is no inhibitory conditioning at all in honeybees--that the only associative function of nonreinforcement is to reduce excitatory strength.     

Acyclophostin: a ribose-modified analog of adenophostin A with high affinity for inositol 1,4,5-trisphosphate receptors and pH-dependent efficacy

The developing legs of Drosophila are subdivided into proximal and distal domains by the activity of the homeodomain proteins Homothorax (Hth) and Distal-less (Dll). The expression domains of Dll and Hth are initially reciprocal. Wingless and Dpp define both domains by activating Dll and by repressing Hth in the distal region of the disc. Wg and Dpp do not act through Dll to repress Hth. Hth functions to reduce the sensitivity of proximal cells to Wg and Dpp. This serves to limit the effective range of these signals in regulating later-acting genes such as Dac. We present evidence that proximal and distal cells tend to sort-out from one another. Cells forced to express Hth are unable to mix with distal cells. Likewise, cells forced to express Dll are unable to mix with proximal cells. Clones of cells unable to express Dll in the distal region sort-out from the disc. Clones of cells unable to express Hth lose the specialized population of cells at the interface between proximal and distal territories and cause fusion between body wall and leg segments. These observations suggest that sorting-out behavior of Hth- and Dll-expressing cells contributes to subdivision of the leg into proximal and distal domains.