P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer.

Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 recruits pleckstrin homology domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anticancer therapeutics targeting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway are in clinical development. In a mass spectrometric screen to identify PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-dependent Rac exchange factor-1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist phosphatase and tensin homolog (PTEN). P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP3-driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in estrogen receptor-positive breast tumors compared with many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells.

Spatial, ontogenetic and interspecific variability in stable isotope ratios of nitrogen and carbon of Merluccius capensis and Merluccius paradoxus off South Africa.

General linear models (GLMs) were used to determine the relative importance of interspecific, ontogenetic and spatial effects in explaining variability in stable isotope ratios of nitrogen (δ(15) N) and carbon (δ(13) C) of the co-occurring Cape hakes Merluccius capensis and Merluccius paradoxus off South Africa. Significant GLMs were derived for both isotopes, explaining 74 and 56% of observed variance in Merluccius spp. δ(15) N and δ(13) C, respectively. Spatial effects (west or south coast) contributed most towards explaining variability in the δ(15) N model, with Merluccius spp. off the west coast having higher (by c. 1.4‰) δ(15) N levels than Merluccius spp. off the south coast. Fish size and species were also significant in explaining variability in δ(15) N, with both species showing significant linear increases in δ(15) N with size and M. capensis having higher (by c. 0.7‰) δ(15) N values than M. paradoxus. Species and coast explained most and similar amounts of variability in the δ(13) C model, with M. capensis having higher (by c. 0.8‰) δ(13) C values than M. paradoxus, and values being lower (by c. 0.7‰) for fishes off the west coast compared with the south coast. These results not only corroborate the knowledge of Merluccius spp. feeding ecology gained from dietary studies, in particular the ontogenetic change in trophic level corresponding to a changing diet, but also that M. capensis feeds at a slightly higher trophic level than M. paradoxus. The spatial difference in Merluccius spp. δ(15) N appears due to a difference in isotopic baseline, and not as a result of Merluccius spp. feeding higher in the food web off the west than the south coast, and provides new evidence that corroborates previous observations of biogeographic differences in isotopic baselines around the South African coast. This study also provides quantitative data on the relative trophic level and trophic width of Cape hakes over a large size range that can be used in ecosystem models of the southern Benguela.

Neural activity in speech-sensitive auditory cortex during silence.

That auditory hallucinations are voices heard in the absence of external stimuli implies the existence of endogenous neural activity within the auditory cortex responsible for their perception. Further, auditory hallucinations occur across a range of healthy and disease states that include reduced arousal, hypnosis, drug intoxication, delirium, and psychosis. This suggests that, even in health, the auditory cortex has a propensity to spontaneously "activate" during silence. Here we report the findings of a functional MRI study, designed to examine baseline activity in speech-sensitive auditory regions. During silence, we show that functionally defined speech-sensitive auditory cortex is characterized by intermittent episodes of significantly increased activity in a large proportion (in some cases >30%) of its volume. Bilateral increases in activity are associated with foci of spontaneous activation in the left primary and association auditory cortices and anterior cingulate cortex. We suggest that, within auditory regions, endogenous activity is modulated by anterior cingulate cortex, resulting in spontaneous activation during silence. Hence, an aspect of the brain's "default mode" resembles a (preprepared) substrate for the development of auditory hallucinations. These observations may help explain why such hallucinations are ubiquitous.

Gambling as an addictive disorder among athletes: clinical issues in sports medicine.

This article examines the role of gambling as an addictive disorder experienced by athletes, both college and professional. Gambling may often be seen as a comorbid factor with other addictions and with depression among athletes. The focus on addictions among athletes has gained considerable attention among sports medicine clinicians. Diagnostic indicators, risk and protective factors, and a stage model of addiction among athletes are addressed. An algorithm and pathway of care for athletes with an addictive disorder is offered as are recommendations that sports physicians, sports medicine specialists, coaches and counsellors need to address athletes who have an addictive disorder.

Violence in the schools: clinical issues and case analysis for high-risk children.

School violence in rural communities has gained considerable attention nationally. Examined are theoretical considerations involving escape theory, the risk and protective factors for school violence, case analyses of recent case studies, and discussion of recent school violence involving fatal injuries to others. Also discussed are diagnostic issues in understanding children who are at-risk for school violence and ways school violence maybe managed in the schools. Suggestions and recommendations including recommendations provided by the National School Safety Center for school personnel are offered, as are steps to be taken in creating a safe school environment. This information may be helpful to child psychiatry and clinical personnel who provide services to school aged children.

Sports medicine in the new millennium: a vision for 2020.

Globalisation, empowerment and technological change will determine the emerging directions in sports medicine in the new millennium. Networks and alliances of scientist and clinician services, as well as electronic profiling of athletes' learning styles, genetic predisposition and other variables, will enhance the spectrum of sports medicine services. Visionary direction will require changes in the organisational paradigms employed, the communication of information to athletes and coaches and the methodologies of assessment. An emphasis on prevention science and clinical and educational interventions will require a clearer focus. The sports medicine scientist and clinician of today must utilise the endowments suggested by Covey and the multiple intelligence models advanced by Gardner in capturing the clarity of focus for sports medicine in the new millennium.

An adolescent vampire cult in rural America: clinical issues and case study.

The emergence of cult related activities in rural America are examined. Cults and their attraction to adolescents are addressed as are methods of cult indoctrination and a profile of cult members and their leader. Clinical management along with a rationale for the attraction of some adolescents to cults are discussed. A case study of a vampire cult and the psychopathology identified in the leader of the cult are provided. Import for clinicians is offered.

Clinical and cultural issues in diagnosing and treating child victims of peer abuse.

Examined are clinical and cultural issues in assessing and treating child victims of peer abuse. Profiles for both victims and perpetrators are discussed as are clinical patterns that may emerge in adulthood. Clinical trauma accommodation is discussed to offer the processing and adaptation to peer victimization. A clinical algorithm is discussed to provide the clinician with a pathway for assessment, treatment and follow-up for children who experience peer victimization.

Posttraumatic stress disorder after treatment for breast cancer: prevalence of diagnosis and use of the PTSD Checklist-Civilian Version (PCL-C) as a screening instrument.

The presence of a posttraumatic stress disorder (PTSD) diagnosis in women (n = 82) diagnosed with Stage 0-IIIA breast cancer was assessed 6 to 72 months after cancer therapy. The PTSD Checklist-Civilian Version (PCL-C) and the PTSD module for the Structured Clinical Interview for DSM-IV, Nonpatient Version, PTSD module (SCID-NP-PTSD) were administered in a telephone interview. SCID-NP-PTSD results indicated prevalence rates of 6% and 4% for current and lifetime PTSD, respectively. Use of the recommended cutoff score of 50 on the PCL-C to determine diagnosis of current cancer-related PTSD resulted in a sensitivity of .60 and a specificity of .99 with 2 false-negative diagnoses. In conclusion, PTSD can be precipitated by diagnosis and treatment of breast cancer, and the PCL-C can be a cost-effective screening tool for this disorder.

Head injury in the presence of alcohol intoxication.

The difficulty of distinguishing between serious head injury and intoxication is presented in the case of an injured patient whose signs and symptoms were attributed to alcohol withdrawal. This report emphasizes the need for a high level of suspicion for all trauma patients, for all health care providers to be familiar with common forms of life-threatening trauma, and how to distinguish between altered levels of consciousness resulting from alcohol intoxication versus intracranial disorders. This case may also demonstrate that a person's wealth and social influence and an institution's orientation to a medical specialty can affect care giver's decisions.

Anniversary reactions in a five-year-old boy. Unresolved conflict, guilt, and self-identifications.

This paper examines the important role of anniversary reactions in the psychological adjustment of seriously traumatized individuals. The clinical case study examines the impact of anniversary reactions on the posttraumatic symptoms and accommodation of a five-year-old boy. Unresolved conflict with the mother, an intense sense of guilt, and difficulty in self-identification were explored during subsequent sessions of psychoanalysis. The clinical significance of considering the possibility of anniversary reactions in children manifesting repetitive attempts of trauma mastering is discussed.

Temephos distribution and persistence in a southwest Florida salt marsh community.

The distribution and persistence of the mosquito larvicide temephos was monitored throughout an intertidal salt marsh community in southwest Florida following routine aerial applications of Abate 4-E (43% temephos) from 1988 through 1993. Temephos was found to be more highly concentrated in the surface water microlayer than in mid-depth water, exhibiting a mean of 330 micrograms/liter at the surface and 12 micrograms/liter at mid-depth from 1 fl. oz./acre applications and 120 micrograms/liter in the surface and 4.5 micrograms/liter in mid-depth water for 0.5 fl. oz./acre applications. Concentrations at both surface and mid-depth diminished rapidly within the first 24 hours. Mangrove leaves provided the most persistent reservoir for temephos, remaining more than 7 days. Temephos residues also were observed in select salt marsh organisms, including the sheepshead minnow (Cyprinodon variegatus), adult fiddler crabs (Uca rapax) and the ribbed mussel (Geukensia sp.).

Baseline assessment of children traumatized by the Armenian earthquake.

Assessed at baseline for longitudinal study is the impact of the Armenian earthquake on children screened through the Children's Psychotherapy Center in Kirovakan, Armenia. The earthquake caused close to 25,000 deaths, almost two thirds of which were children and adolescents. Examined herein are memory functioning and clinical data collected on a baseline level which provides a better understanding of both diagnostic indicators and trauma processing in child survivors of the Armenian earthquake. Current theory related to processing of trauma in children is reviewed as are recommendations for further research.

Subcellular calcium pools of ischaemic and reperfused myocardium characterised by electron probe.

OBJECTIVE: The subcellular redistribution of calcium and other electrolytes was analysed in myocardium subjected to global ischaemia and reperfusion in order to establish possible causes of reperfusion injury. METHODS: Isolated ferret papillary muscles (maintained at 37 degrees C, 1.2 Hz stimulation) were exposed to ischaemic conditions for 1 h by isolating from room air, removing buffer, and exposing to a constant flow of water-saturated 95% N2/5% CO2 gas. Some muscles were "reperfused" for 5 min by exposing to control buffer. Electron probe microanalysis was used to measure subcellular electrolyte content. RESULTS: Ischaemia caused severe swelling and doubling of cell sodium [84(SEM 5) to 156(9) mmol.kg-1 dry weight (dw), P < 0.05]. Mitochondrial electrolyte concentrations were generally increased, most notably calcium [0.40(0.15) to 1.99(0.32) mmol.kg-1 dw, P < 0.05]. Electrolytes in other structures were more moderately affected. Reperfusion resulted in two general myocyte populations. Irreversibly injured cells exhibited contracture knots and an influx of extracellular fluid. Analysis was restricted to moderately injured cells, which had reduced swelling and varying numbers of vacuolated mitochondria. In the moderately injured cells, sodium remained high [167(11) mmol.kg-1 dw] and magnesium had increased from 39(2) to 52(2) mmol.kg-1 dw (P < 0.05). Mitochondrial calcium was near control levels [0.64(0.42) mmol.kg-1 dw]. Junctional sarcoplasmic reticular calcium significantly increased [6.56(0.59) to 18.53(1.64) mmol.kg-1 dw in control and reperfused cells, respectively, P < 0.05], while calcium had not changed significantly in T tubule lumen or "3rd compartment", composed of sarcoplasmic reticulum, T tubules, and free sarcoplasm. "3rd compartment" and junctional sarcoplasmic reticulum results suggest that sarcolemma bound calcium had decreased. CONCLUSIONS: Surviving myocytes had no change in total calcium, but showed a large degree of calcium redistribution. Mitochondria accumulated calcium during ischaemia, but released it upon reperfusion. Sarcoplasmic reticulum in reperfused cells appeared functional and may have helped maintain physiological [Ca2+]i by storing calcium released from mitochondria and the sarcolemma. Mitochondrial and sarcolemmal damage are proposed as critical factors in reperfusion injury.

Clinical and preventive issues in child custody disputes.

Clinical efforts in child custody disputes have emphasized preventive measures that address the best interests of the child. Examined herein is the impact of separation and divorce on families and preventive oriented efforts in contested child custody family mediation models. Also addressed are psychological factors in mediation, an identified model of family mediation, and clinical issues in the contested child custody arena.

Assessment of sexual abuse and trauma: clinical measures.

Examined are several measures currently used in the assessment of child abuse, sexual abuse, and trauma. These measures include structured clinical interviews, self report measures, screening inventory, symptom checklist, and some measures that include decision making properties. Issues and implications for clinical practice are explored.

Aedes albopictus distribution, abundance, and colonization in Lee County, Florida, and its effect on Aedes aegypti.

In 1992 the known southern limit of Aedes albopictus in Florida was in Lee County. Through oviposition surveillance, the distribution of Ae. albopictus was determined, and its frequency relative to Aedes aegypti and colonization pattern of areas previously occupied by Ae. aegypti were examined in Lee County. The data collected in the first year of surveillance demonstrate the ability of Ae. albopictus to rapidly and preferentially colonize large expanses of rural southwest Florida. Urban and suburban areas of the county showed slower colonization rates. In suburban areas, Ae. albopictus became the dominant container-breeding mosquito species, whereas it did not become dominant in urban areas. During the study period, Ae. albopictus did not displace Ae. aegypti in urban or suburban habitats. The southern limit of Ae. albopictus moved a distance of 8.1 km (5 mi.) in 6 wk to the southern border of the county.

Adult non-survivors: the failure to cope of victims of child abuse.

The long-term effects of child abuse have received significant attention in the research. The adult who is so affected by the trauma of child abuse is less often studied. The adult non-survivor experiences considerable and ultimately massive decompensation and failure in the ability to cope with and adjust to adult stresses. A case study is presented to illustrate this phenomenon. Issues for clinical practice and further research are identified.

Family violence: clinical indicators among military and post-military personnel.

Child and spouse abuse continues to be a critically important problem for the medical and mental health professions. Examined are recent clinical data and research addressing this most serious concern among military and post-military personnel. Criteria useful in the identification of risk persons and diagnosis and treatment of family violence are discussed. Specific attention is given to the diagnostic indicators, the abusing family profile, the traumatic process of abuse, and strategies relevant to psychiatric intervention. Guidelines for military mental health and medical professionals are explored.