The ears of butterflyfishes (Chaetodontidae): 'hearing generalists' on noisy coral reefs?

Analysis of the morphology of all three otolithic organs (sacculus, lagena and utriculus), including macula shape, hair cell morphology, density, orientation pattern, otolith morphology and the spatial relationships of the swimbladder and ear, reveals that butterflyfishes in the genera Chaetodon (which has anterior swimbladder horns) and Forcipiger (which lacks anterior swimbladder horns) both demonstrate the ear morphology typical of teleosts that lack otophysic connections, fishes that have traditionally been considered to be 'hearing generalists'.

Reliability and validity of the Visual Gait Assessment Scale for children with hemiplegic cerebral palsy when used by experienced and inexperienced observers.

This study investigated the reliability and validity of the Visual Gait Assessment Scale when used by experienced and inexperienced observers. Four experienced and six inexperienced observers viewed videotaped footage of four children with hemiplegic cerebral palsy on two separate occasions. Validity of the Scale was obtained by comparison with three-dimensional gait analysis (3DGA). The experienced observers generally had higher inter-observer and intra-observer reliability than the inexperienced observers. Both groups showed higher agreement for assessments made at the ankle and foot than at the knee and hip. The experienced observers had slightly higher agreement with 3DGA than the inexperienced observers. The inexperienced observers showed a learning effect and had higher inter-observer agreement and higher agreement with 3DGA in the second assessment of the videotapes. This scale can be used by inexperienced observers but is limited to observations in the sagittal plane and by poor reliability at the knee and hip for experienced and inexperienced observers.

The use of turbulent flow chromatography and the isocratic focusing effect to achieve on-line cleanup and concentration of neat biological samples for low-level metabolite analysis.

The use of turbulent flow chromatography in conjunction with column switching isocratic focusing was used to perform on-line sample cleanup and concentration of neat rat plasma for the identification of low-level metabolites. The concentration was achieved by focusing multiple injections, which were cleaned by a turbulent flow column, onto an analytical column prior to elution into the mass spectrometer. In addition, the first application of turbulent flow chromatography for on-line sample cleanup of neat bile samples is reported. The on-line cleanup and concentration method extracts and concentrates a sample 20-fold in 1 h, and is completely automated.

Generic method for on-line extraction of drug substances in the presence of biological matrices using turbulent flow chromatography.

The use of liquid chromatography/mass spectrometry (LC/MS) to quantify drugs in biological matrices has been well established over the last decade. Extremely fast LC/MS methods are commonplace in the pharmaceutical industry for high-throughput Absorption, Distribution, Metabolism and Excretion (ADME) screening. However, to truly take full advantage of high-throughput ADME screening, a generic method is needed that eliminates the need to develop a new method for each new compound being screened. New developments in the stationary phase of turbulent flow columns has allowed us to develop an on-line biological sample cleanup method that is suitable for over 99% of the compounds in the Cephalon database.

Disposition of the novel anti-schizophrenic drug [14C]olanzapine in male Fischer 344 and female CD rats following single oral dose administration.

These studies comprehensively evaluate the distribution of [14C]olanzapine (2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno(2,3-b)-1,5)benzodiazepin e, CAS 132539-06-1, LY170053) a novel anti-schizophrenic compound, following single oral dose administration in male Fischer 344 rats, and pregnant and non-pregnant lactating female CD rats. The disposition of radiocarbon was determined and tissue pharmacokinetics evaluated in male Fischer 344 rats following a single oral 8 mg/kg dose at 2, 6, 24, 48, 72, and 96 h postdose using quantitative whole-body autoradiographic (QWBA) techniques in conjunction with image analysis. This study demonstrated that [14C]olanzapine and/or metabolites were rapidly absorbed and widely distributed with a tmax of 2 h postdose in most tissues. Persistent but declining concentrations of radiocarbon were detected in feces, kidney, liver, and Harderian, preputial, and thyroid glands at 96 h postdose. Placental transfer of [14C]olanzapine was evaluated at 0.5, 1, 3, 6, and 24 h postdose on gestation day 12, the mid-point of organogenesis, by tissue dissection and liquid scintillation spectroscopy (LSC) and on gestation day 18, a time which enabled visualization of fetal tissues by whole-body autoradiography (WBA). The placental transfer studies indicated that all tissues analyzed had a tmax of 1 or 3 h postdose with maternal liver consistently containing high concentrations of radiocarbon. Embryos contained measurable concentrations of radiocarbon throughout the time course of these studies confirming that [14C]olanzapine and/or its metabolites crossed the placenta. Additionally, the disposition of [14C]olanzapine in milk and plasma of lactating female CD rats confirmed pup exposure through milk ingestion.

Quantitative whole-body autoradiography in pregnant rabbits to determine fetal exposure of potential teratogenic compounds.

Whole-body autoradiography (WBA) allows the determination of sites of accumulation and differential distribution of radiolabeled compounds within organs. WBA is routinely conducted in pregnant rats to evaluate placental transfer and fetal distribution of potential developmental toxins. This technique has recently been adapted to evaluate tissue distribution in the pregnant rabbit, which may be a more appropriate model for some pharmaceutical candidates. A preliminary WBA study was conducted on New Zealand white (NZW) rabbits at gestation day 18, 1 h following a single oral dose of 14C-glucose. The purpose of this study was to validate the use of WBA techniques in assessing the placental transfer of compounds in pregnant rabbits. Antiviral compound LY217896 sodium demonstrated developmental toxicity in the pregnant NZW rabbit following multiple oral doses of 10 mg/kg on gestation days 6 through 18. WBA techniques were used to determine the distribution of radiocarbon 30 minutes following a single oral 10-mg/kg dose of 14C-LY217896 sodium in pregnant NZW rabbits on gestation day 18.

Prodrug esters of the indolocarbazole CEP-751 (KT-6587).

Prodrug esters of the indolocarbazole CEP-751 (KT-6587) were prepared with the goal of identifying water soluble, stable but cleavable forms for intravenous dosing. A dipeptide proform Lys-beta-Ala (16, CEP-2563/KT-8391) was identified for advancement to clinical trials.

Adult memories of childhood trauma: a naturalistic clinical study.

The clinical evaluations of 77 adult psychiatric outpatients reporting memories of childhood trauma were reviewed. A majority of patients reported some degree of continuous recall. Roughly half (53%) said they had never forgotten the traumatic events. Two smaller groups described a mixture of continuous and delayed recall (17%) or a period of complete amnesia followed by delayed recall (16%). Patients with and without delayed recall did not differ significantly in the proportions reporting corroboration of their memories from other sources. Idiosyncratic, trauma-specific reminders and recent life crises were most commonly cited as precipitants to delayed recall. A previous psychotherapy was cited as a factor in a minority (28%) of cases. By contrast, intrusion of new memories after a period of amnesia was frequently cited as a factor leading to the decision to seek psychotherapy. The implications of these findings are discussed with respect to the role of psychotherapy in the process of recovering traumatic memories.

Dissociation, somatization, and affect dysregulation: the complexity of adaptation of trauma.

OBJECTIVE: A century of clinical research has noted a range of trauma-related psychological problems that are not captured in the DSM-IV framework of posttraumatic stress disorder (PTSD). This study investigated the relationships between exposure to extreme stress, the emergence of PTSD, and symptoms traditionally associated with "hysteria," which can be understood as problems with stimulus discrimination, self-regulation, and cognitive integration of experience. METHOD: The DSM-IV field trial for PTSD studied 395 traumatized treatment-seeking subjects and 125 non-treatment-seeking subjects who had also been exposed to traumatic experiences. Data on age at onset, the nature of the trauma, PTSD, dissociation, somatization, and affect dysregulation were collected. RESULTS: PTSD, dissociation, somatization, and affect dysregulation were highly interrelated. The subjects meeting the criteria for lifetime (but not current) PTSD scored significantly lower on these disorders than those with current PTSD, but significantly higher than those who never had PTSD. Subjects who developed PTSD after interpersonal trauma as adults had significantly fewer symptoms than those with childhood trauma, but significantly more than victims of disasters. CONCLUSIONS: PTSD, dissociation, somatization, and affect dysregulation represent a spectrum of adaptations to trauma. They often occur together, but traumatized individuals may suffer from various combinations of symptoms over time. In treating these patients, it is critical to attend to the relative contributions of loss of stimulus discrimination, self-regulation, and cognitive integration of experience to overall impairment and provide systematic treatment that addresses both unbidden intrusive recollections and these other symptoms associated with having been overwhelmed by exposure to traumatic experiences.

Crime and memory.

The conflict between knowing and not knowing, speech and silence, remembering and forgetting, is the central dialectic of psychological trauma. This conflict is manifest in the individual disturbances of memory, the amnesias and hypermnesias, of traumatized people. It is manifest also on a social level, in persisting debates over the historical reality of atrocities that have been documented beyond any reasonable doubt. Social controversy becomes particularly acute at moments in history when perpetrators face the prospect of being publicly exposed or held legally accountable for crimes long hidden or condoned. This situation obtains in many countries emerging from dictatorship, with respect to political crimes such as murder and torture. It obtains in this country with regard to the private crimes of sexual and domestic violence. This article examines a current public controversy, regarding the credibility of adult recall of childhood abuse, as a classic example of the dialectic of trauma.

Isolation and pharmacological characterization of omega-grammotoxin SIA, a novel peptide inhibitor of neuronal voltage-sensitive calcium channel responses.

omega-Grammotoxin SIA, a peptidergic blocker of voltage-sensitive calcium channel (VSCC) responses, was purified from Grammostola spatulata (tarantula spider) venom by reverse phase high performance liquid chromatography. Protease-sensitive biological activity was monitored by determining the inhibition of K(+)-stimulated influx of 45Ca2+ into rat brain synaptosomes. Electrospray mass spectrometry indicated an average molecular mass of 4109.2 Da for the native peptide. Chemical reduction of omega-grammotoxin SIA indicated the presence of three disulfide bridges. Primary sequence data confirmed the existence of six cysteine residues and 36 residues in total, with an average theoretical molecular mass of 4109.7 Da for the amidated carboxyl-terminal species. The biological profile of omega-grammotoxin SIA indicated virtually complete blockade of presynaptic vertebrate N-type as well as P-type VSCC responses. Specifically, omega-grammotoxin SIA caused a concentration-dependent and virtually complete inhibition of K(+)-evoked influx of 45Ca2+ into either rat or chick brain synaptosomes. Similar inhibition profiles were generated for the inhibition of release of either D-[3H]aspartate or [3H]norepinephrine from rat hippocampal or [3H]norepinephrine from chick cortical brain slice preparations evoked by K+ depolarization. As reported earlier, omega-grammotoxin SIA did not inhibit 125I-omega-conotoxin GVIA, [3H]PN 200-110, or [3H]desmethoxyverapamil binding to neuronal membrane fragments. To our knowledge, omega-grammotoxin SIA is the first ligand identified to block putative N-channel function without displacement of 125I-omega-conotoxin GVIA. omega-Grammotoxin SIA thus represents a novel vertebrate VSCC antagonist that inhibits neuronal N- and P-type VSCC responses.

Effects of site-specific acetylation on omega-conotoxin GVIA binding and function.

Chemical modification of omega-conotoxin GVIA (omega-CgTXGVIA) was performed using nonsaturating concentrations of acetic anhydride to generate seven distinct derivatives. Following separation of these peptides using reverse-phase HPLC (RP-HPLC), their individual molecular weights were determined using fast bombardment mass spectrometry (FAB-MS). Three peptides contained a single acetylated amino group, three possessed two acetylated amino groups, and the last contained three acetylations. For each peptide, the specific site of acetylation was confirmed using a scheme of tryptic digestion, under nonreducing conditions, followed by RP-HPLC and FAB-MS. Biological profiles for each peptide were obtained by analyzing their capacity to displace native 125I-omega-CgTx GVIA binding to rat hippocampal membranes and to block K(+)-stimulated 45Ca2+ influx into chick brain synaptosomes. The data indicate that successive additions of acetyl moieties to omega-CgTx GVIA lead to a loss of both binding affinity and Ca2+ influx inhibitory potency. Within the monoacetylated series, acetylation of the amino terminal of Cys-1, as compared to the epsilon-amino group of either Lys-2 or Lys-24, leads to the greatest shift in potency. In summary, these results indicate that basic (i.e., primary amino) groups, which are brought into close proximity as a result of disulfide bridging, are important in the functional blockade of neuronal Ca2+ channels by omega-CgTx GVIA.

Phosphorylation of recombinant tau by cAMP-dependent protein kinase. Identification of phosphorylation sites and effect on microtubule assembly.

Tau protein is an integral component of paired helical filaments, a pathological feature of Alzheimer's disease. tau extracted from these filaments displays decreased electrophoretic mobility due to aberrant phosphorylation. Here we show that recombinant human tau can be phosphorylated by cAMP-dependent protein kinase resulting in decreased electrophoretic mobility. Phosphorylation of tau by cAMP-dependent protein kinase caused a 92% decrease in the maximum rate of tau-induced microtubule assembly. The sites of phosphorylation were identified by digesting phosphorylated tau with proteases, separating the peptides by reversed-phase HPLC, and analyzing the isolated peptides by liquid-secondary ion mass spectrometry and solid-phase N-terminal sequencing. Five phosphorylation sites were identified, two of which were located within microtubule binding domains. One site was previously shown to be the sole phosphorylation site for CaM kinase II; phosphorylation at this site by CaM kinase II was sufficient to cause decreased electrophoretic mobility (Steiner, B., Mandelkow, E. M., Biernat, J., Gustke, N., Meyer, H. E., Schmidt, B., Mieskes, G., Soling, H. D., Drechsel, D., Kirschner, M. W., Goedert, M., and Mandelkow, E. (1990) EMBO J. 9, 3539-3544). Thus two different second messenger-dependent protein kinases can phosphorylate tau at the same site and induce a shift in tau mobility like that seen in Alzheimer's disease.

Psychodynamic aspects of delayed abortion decisions.

Multiple regression analysis of a wide range of variables for a sample of 58 women obtaining elective abortion identified psychodynamic factors as the only statistically significant explanations for seeking abortion at later gestational ages. Delay among these women was associated with greater disturbance in the basic sense of self as noted in indications of gender/sexual conflict on their drawings of a human figure, and lower achievement orientation ('striving') as expressed by lower levels of striving attributed to parents or other primary (early) caretakers. These findings are discussed as an active taking charge of an unintended pregnancy for women who present early for abortion; for those who delay, attempts to affirm a deficient feminine identification and/or reunite psychologically with the early caretaker are discussed as underlying dynamics.

Childhood origins of self-destructive behavior.

OBJECTIVE: Clinical reports suggest that many adults who engage in self-destructive behavior have childhood histories of trauma and disrupted parental care. This study explored the relations between childhood trauma, disrupted attachment, and self-destruction, using both historical and prospective data. METHOD: Seventy-four subjects with personality disorders or bipolar II disorder were followed for an average of 4 years and monitored for self-destructive behavior such as suicide attempts, self-injury, and eating disorders. These behaviors were then correlated with independently obtained self-reports of childhood trauma, disruptions of parental care, and dissociative phenomena. RESULTS: Histories of childhood sexual and physical abuse were highly significant predictors of self-cutting and suicide attempts. During follow-up, the subjects with the most severe histories of separation and neglect and those with past sexual abuse continued being self-destructive. The nature of the trauma and the subjects' age at the time of the trauma affected the character and the severity of the self-destructive behavior. Cutting was also specifically related to dissociation. CONCLUSIONS: Childhood trauma contributes to the initiation of self-destructive behavior, but lack of secure attachments helps maintain it. Patients who repetitively attempt suicide or engage in chronic self-cutting are prone to react to current stresses as a return of childhood trauma, neglect, and abandonment. Experiences related to interpersonal safety, anger, and emotional needs may precipitate dissociative episodes and self-destructive behavior.

Breaking secrecy. Adult survivors disclose to their families.

With families in which incest has occurred, secrecy is the organizing principle of all family relationships. Both the testimony of survivors and the clinical literature emphasize the central role of the incest secret. Children who have been sexually abused by adults outside the family also frequently keep this secret as a result of intimidation or shame. Secrecy compounds the trauma of the sexual abuse itself by isolating the victim from others, so that her perceptions can not be validated. Often, the victim comes to doubt her own experience of reality, which is at odds with the family's version of the truth. Many, if not most, victims of child sexual abuse reach adult life still preserving the rule of secrecy.

Childhood trauma in borderline personality disorder.

Subjects with borderline personality disorder (N = 21) or borderline traits (N = 11) and nonborderline subjects with closely related diagnoses (N = 23) were interviewed in depth regarding experiences of major childhood trauma. Significantly more borderline subjects (81%) gave histories of such trauma, including physical abuse (71%), sexual abuse (68%), and witnessing serious domestic violence (62%); abuse histories were less common in those with borderline traits and least common in the subjects with no borderline diagnosis. These results demonstrate a strong association between a diagnosis of borderline personality disorder and a history of abuse in childhood.

Management and rehabilitation of sexually exploitive therapists.

State legislators and mental health professionals in Minnesota have been active in developing strategies to improve reporting, management, and rehabilitation of sexually exploitive therapists. In 1985 and 1986, the legislature criminalized sexual contact by a therapist with a current or emotionally dependent former patient, established sexual exploitation by a therapist as a statutory cause of action, and required that all licensed health professionals report to the Board of Medical Examiners any physician who engages in sexual or sexually suggestive contact with a patient. The Walk-In Counseling Center, a nonprofit agency in Minneapolis, has taken an active role in evaluating exploitive therapists for licensing boards and employers to determine their rehabilitation potential. Mental health professionals and lawmakers have also collaborated in the development of strategies for preventing sexual exploitation and abuse by therapists.

Psychiatrist-patient sexual contact: results of a national survey, II: Psychiatrists' attitudes.

In a national random-sample survey of 1,423 practicing psychiatrists, the overwhelming majority of the respondents (98%) said that therapist-patient sexual contact is always inappropriate and usually harmful to the patient. However, 29.6% said that such contact after termination of therapy might sometimes be acceptable. Psychiatrists who acknowledged having had sexual contact with one or more patients (N = 84) differed markedly from their peers in their attitudes. The majority (74%) of these offenders believed that sexual contact could be appropriate after termination; many apparently rationalized their behavior in this manner. The authors discuss the need for systematic professional education on the subject.