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A random sample of custody and visitation petitions filed in New York City Family Courts in 1995 was used to examine outcomes of mothers’ Order of Protection (OP) Petitions in relation to parents’ custody and visitation petitions. Fathers restrained by OPs were more likely to secure visitation orders (64%) than not. In contrast, 80.8% of fathers’ custody petitions were dismissed when they were restrained by OPs. Fathers’ custody petitions were most likely to be ordered when mothers’ OP petitions were withdrawn. Mothers were most likely to secure custody when their OP petitions were ordered or withdrawn. Courts rarely denied petitions. Those that did not result in court orders were either withdrawn by the petitioner or dismissed by the court (most likely because of failure of the petitioner to appear in court). This pattern has negative implications for battered women who may be vulnerable to pressure or threats from abusive expartners.

The Portable Fastener Delivery System or PFDS, has been developed at the Boeing St. Louis facility to streamline the manual fastener installation process. The PFDS delivers various fasteners, on demand, through a deliverytube to an installation tool used by the operator to install the fasteners in an aircraft assembly. This paper describes the PFDS in its current configuration, along with the associated Huck® International (now Alcoa Fastening Systems) installation tooling, as it is being implemented on the F/A-18E/F Nosebarrel Skinning application. As a "portable" system, the PFDS cart can be rolled to any location on the shop floor it might be needed. The system uses a removable storage cassette to cache many sizes and types of fasteners in the moderate quantities that might be required for a particular assembly task. The operator begins the installation sequence by calling for the particular fastener grip length needed using a wireless control pendant. The fastener is sent to a Huck® PowerFeed installation tool through a pneumatic delivery tube. The operator manually inserts the fastener into the hole and pulls the tool trigger to activate the hydraulic system and upset the fastener. The PFDS continues to send the same grip fastener to the installation tool until the operator elects to change to another grip size using the pendant. This paper will discuss the existing F/A-18E/F Nosebarrel skinning application, the operation of the PFDS and the operation of the Huck® PowerFeed installation tool. The paper will also discuss how the simplification of the installation process has improved quality and increased production efficiency.

Because low dietary calcium intake may accelerate bone loss, patients often are advised to increase their dietary intake of calcium. However, some patients may be unable to tolerate good calcium sources such as dairy products. We postulated that the calcium content of soups and stews could be increased by prolonged cooking with a beef bone. Three experiments were done to prove this theory: (1) a bone soup made with a beef bone and distilled water, cooked for 24 hours; (2) a bone-vegetable soup cooked the same way; and (3) a vegetable soup made the same way but without the bone. It was concluded that prolonged cooking of a bone in soup increases the calcium content of the soup when cooked at an acidic, but not at a neutral pH.

The relationship of intimate partner violence to psychological distress and the mediating or moderating effects of social support were examined among 99 married active duty Army women and 477 married active duty Army men. Although approximately 40% of both the men and the women had experienced physical partner violence in the past year, in neither group was physical violence correlated with psychological distress when controlling for other variables. Among women, psychological abuse inflicted by a partner was significantly associated with greater psychological distress. Among men, poor marital adjustment was associated with greater psychological distress. An unexpected significant interaction effect was found among women indicating that those who were violent toward their partners under conditions of high peer support experienced greater psychological distress.

A U.S. Army post in Alaska (Fort A) was determined to have a higher than average rate of officially reported cases of spousal abuse compared with the Army as a whole. The purpose of the present study was to determine whether Fort A had a higher rate of self-reported spousal abuse compared with the Army as a whole.A survey on intimate partner violence was conducted among 648 married male personnel who completed a questionnaire that included the Modified Conflict Tactic Scale.Comparisons with results of an earlier study involving a large representative sample of Army personnel indicated that Fort A did not have higher levels of intimate partner violence than the Army average based on soldiers' self-reports.It may not be appropriate to draw conclusions about serious intimate partner violence in the military based solely on the results of family conflict surveys.

Histone deacetylase (HDACs) regulate histone acetylation by catalyzing the removal of acetyl groups on the NH(2)-terminal lysine residues of the core nucleosomal histones. Modulation of the acetylation status of core histones is involved in the regulation of the transcriptional activity of certain genes. HDAC activity is generally associated with transcriptional repression. Aberrant recruitment of HDAC activity has been associated with the development of certain human cancers. We have developed a class of HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), that were initially identified based on their ability to induce differentiation of cultured murine erythroleukemia cells. Additional studies have demonstrated that SAHA inhibits the growth of tumors in rodents. In this study we have examined the effects of SAHA on MCF-7 human breast cancer cells. We found that SAHA causes the inhibition of proliferation, accumulation of cells in a dose-dependent manner in G(1) then G(2)-M phase of the cell cycle, and induction of milk fat globule protein, milk fat membrane globule protein, and lipid droplets. Growth inhibition was associated with morphological changes including the flattening and enlargement of the cytoplasm, and a decrease in the nuclear:cytoplasmic ratio. Withdrawal of SAHA led to reentry of cells into the cell cycle and reversal to a less differentiated phenotype. SAHA induced differentiation in the estrogen receptor-negative cell line SKBr-3 and the retinoblastoma-negative cell line MDA-468. We propose that SAHA has profound antiproliferative activity by causing these cells to undergo cell cycle arrest and differentiation that is dependent on the presence of SAHA. SAHA and other HDAC inhibitors are currently in Phase I clinical trials. These findings may impact the clinical use of these drugs.

The epidermal growth factor receptor (EGFR) is commonly overexpressed in many human tumors and provides a new target for anticancer drug development. ZD1839 ("Iressa"), a quinazoline tyrosine kinase inhibitor selective for the EGFR, has shown good activity in preclinical studies and in the early phase of clinical trials. However, because it remains unclear which tumor types are the best targets for treatment with this agent, the molecular characteristics that correlate with tumor sensitivity to ZD1839 have been studied. In a panel of human breast cancer and other epithelial tumor cell lines, HER2-overexpressing tumors were particularly sensitive to ZD1839. Growth inhibition of these tumor cell lines was associated with the dephosphorylation of EGFR, HER2, and HER3, accompanied by the loss of association of HER3 with phosphatidylinositol 3-kinase, and down-regulation of Akt activity. These studies suggest that HER2-overexpressing tumors are particularly susceptible to the inhibition of HER family tyrosine kinase signaling and suggest novel strategies to treat these particularly aggressive tumors.

17-allyl-aminogeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a highly conserved pocket in the Hsp90 chaperone protein and inhibits its function. Hsp90 is required for the refolding of proteins during cellular stress and the conformational maturation of certain signaling proteins. 17-AAG has antitumor activity in cell culture and animal xenograft models and is currently in clinical trial. It causes an RB-dependent G(1) arrest, differentiation, and apoptosis. RB-negative cells arrest in mitosis and undergo apoptosis. Hsp90 plays an important role in the cellular response to environmental stress. Therefore, we tested whether the regulation of Hsp90 function by 17-AAG could sensitize cells to cytotoxic agents. 17-AAG sensitized tumor cells to Taxol and doxorubicin. Taxanes cause growth arrest in mitosis and apoptosis. The addition of 17-AAG to cells after exposure to Taxol significantly increased both the activation of caspases 9 and 3 and apoptosis. In cells with intact RB, exposure to 17-AAG before Taxol resulted in G(1) arrest and abrogated apoptosis. Schedule dependence was not seen in cells with mutated RB, because both agents blocked cells in mitosis. Schedule- or RB-dependence was also not observed when cells were treated with 17-AAG and doxorubicin, a DNA-intercalating agent that acts on different phases of the cell cycle. These findings suggest that inhibition of Hsp90 function by 17-AAG enhances the apoptotic effects of cytotoxic agents. The sequence of drug administration and the RB status significantly influence efficacy.

17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a conserved pocket in Hsp90 and induces the degradation of proteins that require this chaperone for conformational maturation. 17-AAG causes a retinoblastoma (RB)-dependent G1 block in cancer cells and is now in clinical trial. In breast cancer cells, G1 block is accompanied by differentiation and followed by apoptosis. The differentiation is characterized by specific changes in morphology and induction of milk fat proteins and lipid droplets. In cells lacking RB, neither G1 arrest nor differentiation occurs; instead, they undergo apoptosis in mitosis. Introduction of RB into these cells restores the differentiation response to 17-AAG. Inhibitors of the ras, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways cause accumulation of milk fat proteins and induction of lipid droplets when associated with G1 arrest but do not cause morphological changes. Thus, regulation of Hsp90 function by 17-AAG in breast cancer cells induces RB-dependent morphological and functional mammary differentiation. G1 arrest is sufficient for some but not all aspects of the phenotype. Induction of differentiation may be responsible for some of the antitumor effects of this drug.

The aim of this study was to determine whether early changes in serum markers of bone resorption could predict long-term responses in bone mineral density (BMD) after alendronate therapy in elderly women. One hundred and twenty women (mean age, 70 yr) were randomized to alendronate or placebo in this double blind, placebo-controlled clinical trial for 2.5 yr. Outcome measures were hip and spine BMD and biochemical markers of bone resorption, including serum N-telopeptide and C-telopeptide cross-linked collagen type I (NTx and CTx, respectively). Serum NTx and CTx were highly correlated at baseline (r = 0.73; P0.001) and remained so throughout the study (range, r = 0.36-0.56; all P0.05). After treatment with alendronate, serum NTx decreased 30.4+/-16.0% at 6 months, reaching a nadir of -36.7+/-18.0% by 24 months (P0.001). Serum CTx decreased 43.5+/-67.0% at 6 months and continued to decrease to 67.3+/-19.3% at 2.5 yr (P0.001). Moreover, decreases in serum NTx and CTx at 6 months were correlated with long-term improvements in vertebral BMD at 2.5 yr in patients receiving alendronate therapy (NTx: r = -0.42; CTx: r = -0.31; both P0.05). We conclude that early changes in serum NTx and CTx, markers of bone resorption, predict long-term changes in vertebral BMD in elderly women receiving alendronate therapy and provide a useful tool to assess skeletal health.

The ansamycin antibiotics, herbimycin A (HA) and geldanamycin (GM), bind to a conserved pocket in heat shock protein 90 (Hsp90) and alter the function of this chaperone protein. Occupancy of this pocket results in the degradation of a subset of signaling molecules. These include proteins known to associate with Hsp90, e.g., the steroid receptors and Raf, as well as certain transmembrane tyrosine kinases, such as the ErbB receptor family. In a variety of tumor cell lines, treatment with HA potently inhibited cellular proliferation by inducing G1 arrest. This arrest was accompanied by hypophosphorylation of the retinoblastoma gene product (RB) and rapid down-regulation of cyclin D- and E-associated kinase activities. Inhibition of kinase activity was found to result from loss in expression of cyclins D1, D3, and E, as well as the associated cyclin-dependent kinases, cyclin-dependent kinase 4 and cyclin-dependent kinase 6. In addition, HA treatment also caused a late induction of p27(Kip1) protein. The loss of cyclin D preceded the other effects of HA, suggesting that it might be the primary cause of G1 arrest. To determine whether the effects of HA are mediated by selective inhibition of the cyclin D-RB pathway, HA was added to tumor cell lines lacking functional RB. HA treatment of Rb-negative tumor cell lines failed to elicit a G1 arrest. In addition, after release from synchronization with nocodazole, Rb-negative but not Rb-positive cell lines were able to progress through G1 into S phase in the presence of HA. Together, these findings suggest that induction of G1 arrest by HA results from down-regulation of cyclin D expression and its associated kinase activity. Furthermore, these findings imply that Hsp90 selectively regulates signaling pathways upstream of RB.

Few clinicians in the United States use computers during patient encounters and many still worry that computers will depersonalize their interactions with patients. This case study describes patient and clinician reactions to a computer-based health appraisal system. Findings showed no difference in any aspect of patient satisfaction between computer and non-computer groups. Use of a computer in the consulting room neither depersonalized nor enhanced patient satisfaction. Clinicians (in this case, nurse practitioners and physician assistants) were willing to use the system, which they perceived as having benefits for patient care, but were concerned about the increased time required for exams, effort required to learn the system while still interacting appropriately with the patient, increased monitoring of their performance, and other organizational issues. Clinicians who used the system showed a higher tolerance for uncertainty and communicated more frequently with each other and with others throughout the department. Implementation was slowed by the need to demonstrate the monetary value of the system.

Purpose To report the treatment and histopathological findings in two cases who developed eyelid swelling, proptosis and diplopia due to orbital and lid lipogranuloma after endoscopic surgery of the maxillary and ethmoidal sinuses. Methods To relieve the proptosis and diplopia, debulking surgery was done on the eyelids and orbit. The tissue removed was sent for histopathological examination. Results The two patients improved after surgery. The eyelid swelling, proptosis and diplopia subsided and ocular movements became normal. Histopathologic examination disclosed an extensive lipogranuloma. Conclusions Extensive orbital and eyelid lipogranuloma causing proptosis and diplopia is a rare complication of endoscopic sinus surgery, and can be relieved by surgical debulking.

Geldanamycin (GM) is a natural antibiotic that binds Hsp90 and induces the degradation of receptor tyrosine kinases, steroid receptors, and Raf. It is a potent inhibitor of cancer cells that overexpress HER-kinases, but its effects on other important proteins may cause significant toxicity and limit its clinical use. We report the synthesis and identification of a GM dimer, GMD-4c, which had selective activity against HER-kinases. Selectivity was a function of linker length and required two intact GM moieties. GMD-4c is a potent inducer of G1 block and apoptosis of breast cancer cell lines that overexpress HER2, but does not appreciably inhibit the growth of 32D cells that lack HER-kinases. GMD-4c could be useful in the treatment of carcinomas dependent on HER-kinases.

Personality characteristics associated with successful adaptation to military life are often described in gender-related terms. However, valid, reliable measures of gender-related personality characteristics have not been established for military populations. The purpose of this study was to validate an instrument for measuring gender-related personality characteristics in an active duty population. The Extended Personal Attributes Questionnaire was administered to 1,060 male soldiers and 305 female soldiers in U.S. Army support units. Results of a factor analysis indicated that there are three separate factors. The first denotes negatively valued aggressive traits (Negative Masculinity), the second denotes negatively valued passive traits (Negative Femininity), and the third combines positive instrumental and positive expressive traits, referred to as the Combined factor. Although positive instrumental traits (referred to as Masculinity) were related to fewer psychological symptoms, Negative Masculinity and Negative Femininity were associated with increased psychological symptoms. Positive expressive traits (referred to as Femininity) were unrelated to psychological symptoms.

The effects of work climate, pregnancy transitions stress, maternal medical conditions, health risk behaviors, psychological health, and demographic characteristics were examined among 269 pregnant military women. The study found that single and separated/divorced military women were at greater risk for preterm delivery than married women. Unmarried participants were more likely to belong to ethnic minorities, were lower ranking, less educated, and reported a greater number of medical conditions than married participants. Psychosocial variables distinguished the three marital status groups--married, single, and separated/divorced--but none of these variables was related to preterm delivery. In a logistic regression analysis, marital status was a more significant predictor of preterm delivery than were medical conditions.

src kinase activity is elevated in some human tumors, including breast and colon cancers. The precise cellular function of the src family kinases is not clearly understood, but they appear to be involved in numerous signaling pathways. We studied the effects of PD173955, a novel src family-selective tyrosine kinase inhibitor, on cancer cell lines and found that it has significant antiproliferative activity due to a potent arrest of mitotic progression. The mitotic block occurs after chromosome condensation in prophase, before spindle assembly and without loss of cyclin A and B kinase activities. This effect is seen in cancer cell lines of all types with low or high activities of src kinases as well as in untransformed cell lines. In MDA-MB-468 breast cancer cells, this drug produces a rapid inhibition of cellular src and yes kinase activities as well as suppression of the mitotic hyperactivity of these kinases. This compound defines a novel class of antimitotic drugs that work through inhibition of src kinases and possibly other protein kinases that are required for progression through the initial phases of mitosis.

Three hundred ninety-seven Army wives located in Germany, California, and Texas answered a series of questions on seasonal changes in mood and behavior as part of a general health survey. Subjects living in Germany reported significantly more symptoms associated with winter seasonal effective disorder than those living in Texas or California.

This study compares perceptions of stress, cohesion, and psychological well-being among 856 male soldiers and 169 female soldiers from combat support and combat service support units deployed to the Persian Gulf during Operation Desert Storm. Three different types of stressors were measured: anticipation of combat, operational stress, and personal stress. Female soldiers scored higher than male soldiers on all three measures of stress but scored lower than males on horizontal and vertical cohesion. In a stepwise discriminant function analysis, anticipation of combat was the most significant discriminator between the genders, followed by horizontal cohesion. Anticipation of combat was a significant predictor of increased psychological symptoms for both genders, but it had a greater effect on the psychological symptoms of female soldiers compared with male soldiers.

Four different types of childhood maltreatment were examined as predictors of unwanted sexual experiences and acknowledged sexual harassment among male and female active duty soldiers in the United States Army. Predictor variables included childhood sexual abuse, physical-emotional abuse, physical neglect, and emotional neglect. Three types of unwanted sexual experiences in the workplace were examined as outcome variables: gender harassment, unwanted sexual attention, and coercion. Both sexual and physical-emotional abuse during childhood were found to be predictors of unwanted sexual experiences and of acknowledged sexual harassment in the workplace. Among female soldiers, the most severe type of unwanted experience-coercion-was predicted only by childhood physical-emotional abuse. Among male soldiers childhood sexual abuse was the strongest predictor of coercion. A greater variety of types of childhood maltreatment predicted sexual harassment outcomes for male soldiers. Childhood maltreatment and adult sexual harassment were predictors of psychological well-being for soldiers of both genders.

This paper is a preliminary analysis of the potential for atmospheric thermal pollution from a man-made reservoir. The specific site for the study is a proposed hydroelectric project on the Sogamoso River in Colombia, S.A. The region is agricultural with the two staple crops being coffee and cocoa. These two crops are sensitive to both high temperatures and more dramatically to high humidity levels. Farmers from the region are concerned that the construction of the reservoir will negatively impact crop yield. We have used a numerical atmospheric model to simulate weather from the region both without and with the proposed reservoir. Simulations show the magnitude of the impact is too small to be of consequence to crop yield. With these results we draw conclusions about the potential impact of the reservoir on climate. This paper provides a brief introduction to the theory behind the climatic consequences of a large lake. Results are then discussed for two time periods, one during the rainy growing season and one during the dry season. One of the biggest uncertainties in the model boundary conditions arises from the specification of the lake temperature, so the sensitivity of the model to lake temperature is analyzed for one of the study dates. Finally it is shown how a small set of weather simulations are used to draw climatic conclusions.

Although the antiresorptive agent alendronate has been shown to increase bone mineral density (BMD) at the hip and spine and decrease the incidence of osteoporotic fractures in older women, few data are available regarding early prediction of long-term response to therapy, particularly with regard to increases in hip BMD. Examining short-term changes in biochemical markers incorporates physiologic response with therapeutic compliance and should provide useful prognostic information for patients. The objective of this study was to examine whether early changes in biochemical markers of bone turnover predict long-term changes in hip BMD in elderly women. The study was a double-blind, placebo-controlled, randomized clinical trial which took place in a community-based academic hospital. One hundred and twenty community-dwelling, ambulatory women 65 years of age and older participated in the study. Intervention consisted of alendronate versus placebo for 2.5 years. All patients received appropriate calcium and vitamin D supplementation. The principal outcome measures included BMD of the hip (total hip, femoral neck, trochanter, and intertrochanter), spine (posteroanterior [PA] and lateral), total body, and radius. Biochemical markers of bone resorption included urinary N-telopeptide cross-linked collagen type I and free deoxypyridinoline; markers of bone formation included serum osteocalcin and bone-specific alkaline phosphatase. Long-term alendronate therapy was associated with increased BMD at the total hip (4.0%), femoral neck (3.1%), trochanter (5.5%), intertrochanter (3.8%), PA spine (7.8%), lateral spine (10.6%), total body (2.2%), and one-third distal radius (1.3%) in elderly women (all p < 0.01). In the placebo group, bone density increased 1.9-2.1% at the spine (p < 0.05) and remained stable at all other sites. At 6 months, there were significant decreases in all markers of bone turnover (-10% to -53%, p < 0.01) in women on alendronate. The changes in urinary cross-linked collagen at 6 months correlated with long-term bone density changes at the hip (r = -0.35, p < 0.01), trochanter (r = -0.36, p < 0.01), PA spine (r = -0.41, p < 0.01), and total body (r = -0.34, p < 0.05). At 6 months, patients with the greatest drop in urinary cross-linked collagen (65% or more) demonstrated the greatest gains in total hip, trochanteric, and vertebral bone density (all p < 0.05). A 30% decrease in urinary cross-linked collagen at 6 months predicted a bone density increase of 2.8-4.1% for the hip regions and 5.8-6.9% for the spine views at the 2.5-year time point (p < 0.05). There were no substantive associations between changes in biochemical markers and bone density in the placebo group. Alendronate therapy was associated with significant long-term gains in BMD at all clinically relevant sites, including the hip, in elderly women. Moreover, these improvements were associated with early decreases in biochemical markers of bone turnover. Early dynamic decreases in urinary cross-linked collagen can be used to monitor and predict long-term response to bisphosphonate therapy in elderly women. Future studies are needed to determine if early assessment improves long-term patient compliance or uncovers poor compliance, thereby aiding the physician in maximizing the benefits of therapy.

This study examines the effects of three types of unwanted sexual experiences in the workplace on the psychological well-being of male and female U.S. Army soldiers, and the mediating or moderating roles of appraisal of sexual harassment, organizational climate, and the sociodemographic profile of victims. A survey was administered to 1,060 male soldiers and 305 female soldiers between May and July, 1995, at three Army posts in the United States. Unwanted sexual experiences were found to be significant predictors of psychological symptoms for male and female soldiers. Certain aspects of organizational climate and appraisal of sexual harassment were also significant predictors of psychological symptoms.

This article describes a rare case of unilateral arhinia (congenital absence of half of the nose), in which total nasal reconstruction was performed. A glass Jones tube was used to create a new nasolacrimal duct connecting the lumen of the existing lacrimal sac to the contralateral normal nasal cavity.

Leptin, a 16-kDa adipocyte-derived protein whose circulating levels reflect energy stores, increases the resting metabolic rate and thermogenesis in rodents. Thyroid hormones also increase the basal metabolic rate, but nothing is known about possible interactions between leptin and thyroid hormone. Activation of beta-adrenergic receptors decreases leptin levels in rodents. To test the hypothesis that thyroid hormones, by causing a "functional hyperadrenergic" state, result in decreased leptin concentrations in humans, we studied 22 normal healthy men before and after the administration of T3 for 1 week to induce moderate hyperthyroidism. Short term thyroid hormone excess does not alter circulating leptin concentrations despite a demonstrated effect on heart rate, systolic blood pressure, cholesterol levels, and metabolic indexes of bone turnover. Elucidation of the apparently separate pathways by which thyroid hormones, beta-agonists, and leptin regulate energy expenditure and food intake may have important implications for our understanding of the mechanisms for regulating energy homeostasis in health and disease.

This study examined the impact of a history of childhood abuse and neglect on soldiers' adaptation to Army life including commitment to the Army, confidence in leaders, and perceptions of unit cohesion and readiness. Childhood abuse and neglect were measured by the 30-item Childhood Trauma Questionnaire (CTQ) which comprises four subscales-sexual abuse, physical-emotional abuse, emotional neglect, and physical neglect. Information was obtained through a survey of 1,051 male soldiers and 305 female soldiers from combat support and combat service support units located at three different Army posts in the United States. The study found that of the four CTQ subscales, emotional neglect was the only variable predicting lower unit cohesion and lower confidence in leaders for both male and female soldiers even after controlling for concurrent psychological symptoms and sociodemographic variables. Emotional neglect during childhood may have a negative impact on soldiers' ability to access social support within their units, a factor that has been shown to prevent psychological breakdown in combat.

One thousand three hundred sixty-five soldiers from the U.S. Army completed a 30-item version of the Childhood Trauma Questionnaire (CTQ) together with four questions on sexual abuse developed for a national survey of U.S. adults. A four-factor solution to the CTQ produced four subscales that were similar to those found in the original study, namely (1) emotional neglect, (2) physical and emotional abuse, (3) sexual abuse, and (4) physical neglect. We found that half of female soldiers reported a childhood history of sexual abuse, compared with one-sixth of male soldiers. Half of both male and female soldiers reported a childhood history of physical abuse. Combined abuse histories were noted in 34% of female and 11% of male soldiers. Abused soldiers reported more psychological symptoms on the Brief Symptom Inventory than nonabused soldiers. The CTQ and screening questions are discussed as possible tools for eliciting histories of abuse from soldiers.

Heregulins (HRGs) induce tyrosine phosphorylation of several members of the erb-B family of receptors. Although originally isolated as the ligands for p185c-erb-2, recent evidence suggests that other receptors of the erbB family, including p180erbB-3 and p180erbB-4, are their true cognate receptors. Stimulation of MDA MB-453 cells with HRG beta 2 resulted in the tyrosine phosphorylation of p185c-erbB-2 and p180erbB-4 in a time- and dose-dependent fashion. This event was accompanied by the formation of multimeric complexes between the activated receptors and SH2-containing proteins. Ligand caused p120-rasGTPase activating protein (GAP), SHC and the p85 subunit of phosphatidylinositol-3'-kinase (PI3K) to be associated with both p185c-erbB-2 and p180erbB-4. In addition, tyrosine phosphorylation of p85-PI3K and SHC, but not of GAP or of its associated p62 and p190 proteins, was also detected. HRG also induced the association of GRB2 with tyrosine phosphorylated p185c-erbB-2, p180erbB-4 and SHC. Activation of mitogen-activated protein kinase (MAPK) (30-fold over untreated controls) was observed upon receptor(s) activation, as it was the induction of the immediate early gene c-fos (200-fold). These observations suggest that p21ras activation plays a role in the HRG pathway. Furthermore, comparative analysis of the binding of p85-PI3K to 185c-erbB-2 and p180erbB-4, revealed a preferential association with activated p180erbB-4. These findings might suggest a model of HRG action in which the relative expression of the various erb-B family members and the partitioning of signal transduction molecules between each type of receptor might determine the nature of the signal elicited by the ligand and the biological response attained.

Farnesyl protein transferase (FPTase) catalyzes the first of a series of posttranslational modifications of Ras required for full biological activity. Peptidomimetic inhibitors of FPTase have been designed that selectively block farnesylation in vivo and in vitro. These inhibitors prevent Ras processing and membrane localization and are effective in reversing the transformed phenotype of Rat1-v-ras cells but not that of cells transformed by v-raf or v-mos. We have tested the effect of the FPTase inhibitor L-744,832 (FTI) on the anchorage-dependent and -independent growth of human tumor cell lines. The growth of over 70% of all tumor cell lines tested was inhibited by 2-20 microM of the FTI, whereas the anchorage-dependent growth of nontransformed epithelial cells was less sensitive to the effects of the compound. No correlation was observed between response to drug and the origin of the tumor cell or whether it contained mutationally activated ras. In fact, cell lines with wild-type ras and active protein tyrosine kinases in which the transformed phenotype may depend on upstream activation of the ras pathway were especially sensitive to the drug. To define the important targets of FTI action, the mechanism of cellular drug resistance was examined. It was not a function of altered drug accumulation or of FPTase insensitivity since, in all cell lines tested, FPTase activity was readily inhibited within 1 h of treatment with the inhibitor. Furthermore, the general pattern of inhibition of cellular protein farnesylation and the specific inhibition of lamin B processing were the same in sensitive and resistant cells. In addition, functional activation of Ras was inhibited to the same degree in sensitive and resistant cell lines. However, the FTI inhibited the epidermal growth factor-induced activation of mitogen-activated protein kinases in sensitive cells but not in two resistant cell lines. These data suggest that the drug does inhibit ras function and that resistance in some cells is associated with the presence of Ras-independent pathways for mitogen-activated protein kinase activation by tyrosine kinases. We conclude that FPTase inhibitors are potent antitumor agents with activity against many types of human cancer cell lines, including those with wild-type ras.

In a multicentre, double-blind, randomized study involving four general hospitals in Israel, the efficacy and safety of ceftriaxone 1 g/day i.v. was compared to that of 2 g/day i.v. in the treatment of moderate to severe community-acquired infections requiring hospitalization. Two hundred and twenty-two patients were enrolled; 112 received intravenous ceftriaxone 1 g/day, and 110 received 2 g/day. The two groups were matched demographically, and their mean APACHE II score (10 points) and mean duration of successful therapy (7 days) were identical. The sites of infection in the 1 g and 2 g groups respectively were lower respiratory tract in 57 versus 51 patients, urinary tract in 31 versus 40 patients, and soft tissue in 24 versus 19 patients. There were no significant differences in clinical outcome between the 1 g and 2 g groups, the outcome being cure in 91% versus 86% of patients, improvement in 3% versus 3% of patients, failure in 3% versus 8% of patients, and relapse in 3% versus 3% of patients. The findings of this study indicate that ceftriaxone 1 g/day is as effective as 2 g/day in the treatment of moderate to severe community-acquired infections. The low-dose form is a more economical means of treating these infections.

The psychological functioning of soldiers with a handicapped child in the family were compared with that of soldiers without such a child through a survey of 443 soldiers. Self-report questionnaires were utilized to measure depressive symptoms, martial adjustment, social supports, stressful life events, military satisfaction, military performance, and coping. Differences between the 147 soldier-parents with a handicapped child and those without were examined using one-way analyses of variance. The results indicated that soldier-parents with a handicapped child showed significantly higher depressive symptoms, including lower scores on coping, less favorable perception of their military skills and abilities, and more pessimistic attitudes about their long-term military career options, than did the comparison group. Differences in marital satisfaction were not found. Also, perceived social supports played a significantly greater role in buffering the effects of stress on marital adjustment among families with a handicapped child than among those without.

In studies of rat bone metabolism, trabecular bone density should be measured. Three established methods of measuring trabecular bone include trabecular bone volume by histomorphometry (BV/TV%), trabecular bone density by peripheral quantitative computerized tomography (pQCT), and areal bone density of trabecular-rich regions by dual x-ray absorptiometry (DXA). We compared the ability of these three methods to discriminate between orchiectomized (orchidectomized) rats and controls. Sixteen male Sprague-Dawley rats (400–425 g) were orchiectomized, and 16 others were controls. In vivo spine bone mineral density (BMD) was measured at the beginning of the study and again after 11 weeks. Rats were sacrificed, and ex vivo BMDs of the right femur and tibia were measured by DXA, followed by trabecular bone density of the right proximal tibia by pQCT. BV/TV% of the left proximal tibia was measured by histomorphometry. Differences between groups were detected by all three methods, but both the magnitude of the difference between groups and the variance of the measurements was much greater for histomorphometry and pQCT than for DXA. Consequently, the statistical significance for the difference between groups was comparable for all three methods. Of the sites measured with DXA, the proximal tibia had the greatest statistical significance for the difference between groups. In summary, all three methods can demonstrate the effect of orchiectomy on trabecular bone. The large differences between groups seen by histomorphometry are also seen by pQCT but not by DXA. We conclude that trabecular bone density by pQCT may be a reasonable surrogate for measurements by histomorphometry.

Bone is an androgen-dependent tissue. It is not known whether normal bony growth and mineralization in males is dependent on testosterone alone, or whether its metabolite, dihydrotestosterone (DHT), also is required. To answer this question, we examined the effect of finasteride, an inhibitor of DHT synthesis, on bone in rats. Three-month-old male rats were treated with placebo, finasteride, or orchidectomy. The bone mineral densities (BMD) of the spine and whole body were measured in vivo by dual x-ray absorptiometry at weeks 0 and 11, and the BMD of the femur and tibia were measured ex vivo at week 11. Histomorphometric analysis was performed on the proximal tibia at week 11. The increase in spine and whole body BMD in finasteride-treated rats did not differ from that in controls, whereas these values were significantly lower in orchidectomized rats. Similarly, the BMD of the femur and tibia and the cancellous bone volume of the proximal tibia in finasteride-treated rats did not differ from those in controls, whereas these values were significantly lower in orchidectomized rats. In summary, bone development and density were normal in rats treated with finasteride. We conclude that selective DHT deficiency is not deleterious to the male rat skeleton.

CompuHx* is an Interactive Health Appraisal System (IHAPS) used in the examining room at Kaiser-Permanente's San Diego Department of Preventive Medicine to record patient information, assist in diagnosis, and provide a legible summary of findings. The purpose of the present project was to examine the impact of computer use in the examining room on patient satisfaction with the Health Appraisal experience. Survey results showed no significant differences in patient satisfaction between patients whose examiners used CompuHx and those whose examiners did not. These findings indicate that, in the eyes of the patients surveyed, clinician use of a computer in the examining room did not depersonalize their relationship with the clinician, nor did it enhance satisfaction with the thoroughness of the exam or confidence in the examiner's findings.

There are many alternative ways of estimating free thyroxine (T4) when thyrotropin screening results are abnormal. In addition to free T4 immunoassays, the menu of most automated immunoassay instruments includes a nonisotopic version of the original triiodothyronine (T3)-uptake assay called "T-uptake." We evaluated the ability of five such assays (Access, ES-300, IMx, Magnum Opus, and Stratus) to accurately estimate the free thyroxine index (FTI) in euthyroid, hyperthyroid, and hypothyroid patients with abnormal concentrations of thyroid hormone-binding proteins, and in patients with nonthyroidal illness. For comparison, we calculated a similar FTI, using either T3-uptake or direct measurement of thyroxine-binding globulin (TBG). Euthyroid reference ranges were comparable. Of euthyroid patients with increased TBG, 12-32% and 5-20% had increased or suppressed FTI, respectively, depending on the T-uptake method used. Except for IMx, 6-35% of hypothyroid patients with increased TBG had inappropriately increased FTI. Patients with nonthyroidal illness had comparable results regardless of the method used, and T-uptake methods were variably affected by known inhibitors of thyroid hormone binding. The most reliable T-uptake method appeared to be the IMx, which, despite claims that it measures all thyroid hormone-binding proteins, correlated best with TBG concentrations.

Patients with severe nonthyroidal illness may have low serum levels of thyroid hormone and thyroid-stimulating hormone (TSH) indistinguishable from levels in patients with pituitary insufficiency. It is often difficult prospectively to rule out pituitary insufficiency in these patients. Our hypothesis was that patients sufficiently ill to have low free thyroxine index (FT4I) and TSH from nonthyroidal illness (euthyroid sick syndrome, or ESS) would have serum cortisol levels high enough to make pituitary insufficiency unlikely. Serum samples from all patients admitted to the Intensive Care Unit during 2 months were screened for low FT4I, and cortisol levels were measured on those samples. Five of five patients with a diagnosis of ESS had unequivocal elevations of serum cortisol (525 nmol/l), arguing against a diagnosis of pituitary insufficiency. Secondary hypothyroidism due to pituitary insufficiency can often be ruled out in patients with severe ESS by documenting appropriate elevated levels of serum cortisol.

Polypeptide growth factors including the insulin-like growth factors (IGFs), insulin, and transforming growth factor-alpha are mitogens for many breast cancer cell lines and may act as regulators of cancer cell growth. In a human breast cancer cell line MCF-7, which expresses IGF-I receptor (IGF-IR), stimulation with insulin or IGFs resulted in autophosphorylation of the IGF-IR in an increased proportion of ras bound to GTP and in the association of phosphatidylinositol 3'-kinase (PI3K) activity and of p85-PI3K with M(r) 185,000 phosphotyrosinylated proteins corresponding in size to insulin/IGF-IR substrates. These events were associated with enhanced proliferation. MDA MB-468 is a human breast cancer cell line which expresses insulin receptor and high levels of epidermal growth factor/transforming growth factor alpha receptor but low levels of IGF-IR. In this cell line, insulin stimulated autophosphorylation of IR at physiological concentrations and promoted the association of PI3K activity and of p85 with phosphotyrosine-containing proteins. Insulin did not, however, induce increased ras.GTP, and the cells exhibited minimal proliferation in response to insulin. Unlike insulin treatment, epidermal growth factor stimulation of MDA MB-468 cells is mitogenic and resulted in increased ras.GTP content, suggesting that the failure of insulin to induce these changes is not due to alterations in these signaling molecules. We conclude that there is a postreceptor defect in insulin signaling in MDA MB-468 which prevents the activation of ras and the induction of mitogenesis. Activation of PI3K by insulin is not sufficient to mediate mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of bone mineral density (BMD) by dual X-ray absorptiometry (DXA) is a precise and accurate way to assess changes in BMD due to a variety of causes. However, the degree of bone loss may vary depending on the skeletal site examined. We postulated that interventions that change bone density would have a different effect on an area rich in trabecular bone, such as the distal femur, than on other subregions of the femur. Male Sprague-Dawley rats (325-350 g) were treated with triiodothyronine (T3), a bisphosphonate (pamidronate), or placebo for 21 days and then sacrificed. Ex vivo BMD of the proximal, distal, mid and total femur were measured by DXA. We found that mean BMD of hyperthyroid rats was significantly lower than controls at all femoral subregions. However, the difference in mean BMD between hyperthyroid and control rats was greatest at the distal femur (8.6%). In rats treated with bisphosphonate, mean BMD was significantly higher than controls at the proximal, distal, and total femur. The difference in mean BMD between controls and rats treated with bisphosphonate was greatest at the distal femur (31.8%). Furthermore, pamidronate (APD)-treated rats had lower mean mid-femur BMD than controls. We conclude that changes in BMD after treatment with bisphosphonate or T3 are greatest at the distal femur subregion, and that treatment with bisphosphonate may cause a slight reduction in mid-femur BMD. Future studies examining changes in BMD in the rat femur after interventions that alter mineral metabolism should include subregion analysis.

The G1 cyclin D1 is amplified in approximately 20% of human breast cancers and is frequently overexpressed as part of an amplicon in these tumors, suggesting a potential role for this gene in the pathogenesis of breast cancer. Although amplification of cyclin D1 occurs in human breast cancer, it is possible that another gene in the amplicon is the relevant oncogene in these cancers. We now report a truncation of the cyclin D1 gene in a human breast cancer cell line, associated with overexpression of a short cyclin D1 mRNA. In a survey of breast cancer cell lines and tumors by Southern blot hybridization, using a 1.2 kb human cyclin D1 cDNA, we observed that genomic DNA derived from the MDA MB-453 cell line contains an extra band in the Bg1II and BamHI digests, suggesting that one allele of gene is altered. Moreover, the altered allele is amplified three-fold relative to the normal allele, and contains a 3' deletion. On Northern analysis, the MDA MB-453 line has a marked increase in 1.1 to 1.3 kb transcripts, which are truncated at the 3' end, in contrast to the normally predominant 4.2 kb transcript. The 1.1-1.3 kb cyclin D1 mRNA has a longer half-life than the 4.2 kb mRNA, indicating that the 3' truncation may contribute an increased stability and therefore an elevated steady-state level of the short mRNA. These alterations in the cyclin D1 gene and mRNA suggest that altered expression of cyclin D1 may be important in the malignant transformation of this cell line, and support the identification of cyclin D1 as a dominant oncogene at 11q13 in human breast cancer.

Merkel cell carcinoma is an infrequent but highly malignant cutaneous neoplasm. In a 73-year-old woman, a Merkel cell carcinoma of the right upper lid developed within 1 month, recurred within a month after its first removal, and metastasized to the parotid 2 months after secondary excision.