Receptor tyrosine kinase Axl is required for resistance of leukemic cells to FLT3-targeted therapy in acute myeloid leukemia.

In acute myeloid leukemia (AML), about 25-30% of patients harbor a constitutively active receptor tyrosine kinase (RTK) FLT3 encoded by a FLT3 allele harboring internal tandem duplication (FLT3-ITD) mutation. The presence of FLT3-ITD correlates with poor prognosis in AML and it makes FLT3 an attractive therapeutic target in AML. Unfortunately, to date small-molecule inhibitors of FLT3 have resulted in only partial and transient clinical responses with residual leukemic blasts resistant to FLT3 inhibitors detected in blood or bone marrow. In this study, we investigated whether the RTK Axl is responsible for resistance of FLT3-ITD(+) AML cells to PKC412 and AC220, FLT3 inhibitors currently under clinical trials for FLT3-ITD(+) AML patients. Upon treatment with PKC412 or AC220, phosphorylation of Axl was significantly enhanced in the FLT3-ITD(+) MV4-11 AML cell line and in primary blasts from a FLT3-ITD(+) AML patient. Consistently, a PKC412-resistant AML cell line and PKC412-resistant primary blasts from FLT3-ITD(+) AML patients had significantly higher levels of constitutively phosphorylated Axl and total Axl when compared with a PKC412-sensitive AML cell line and PKC412-sensitive primary blasts from FLT3-ITD(+) AML patients. We also found that resistance of AML cells against the FLT3 inhibitor PKC412 and AC220 was substantially diminished by the inhibition of Axl via a small-molecule inhibitor TP-0903, a soluble receptor Axl fusion protein Axl-Fc or knockdown of Axl gene expression by shRNA. Collectively, our study suggests that Axl is required for resistance of FLT3-ITD(+) AML cells against the FLT3 inhibitor PKC412 and AC220, and that inhibition of Axl activation may overcome resistance to FLT3-targeted therapy in FLT3-ITD(+) AML.

The impending crisis awaiting cardiac transplantation. Modeling a solution based on selection.

BACKGROUND: Each month, the number of transplant candidates added to the waiting list exceeds the number of transplantations performed, and many outpatients deteriorate to require transplantation urgently. The current list of 2400 candidates and the average wait of 8 months continue to increase. METHODS AND RESULTS: To determine the size at which the outpatient and critical candidate pools will stabilize, population models were constructed using current statistics for donor hearts, candidate listing, sudden death, and outpatient decline to urgent status and revised to predict the impact of alterations in policies of candidate listing. If current practices continue, within 48 months the predicted list will stabilize as the sum of an estimated 270 hospitalized candidates, among whom, together with newly listed urgent candidates, all hearts will be distributed and 3700 outpatient candidates with virtually no chance of transplantation unless they deteriorate to an urgent status. Decreasing the upper age limit now to 55 years would reduce the number listed each month by 30% and result within 48 months in a list of only 1490. The list could also be decreased by 30%, however, if it were possible to list only a candidate group with an 80% chance (compared with 52% estimated currently) of sudden death or deterioration during the next year. With this strategy, the waiting list would equilibrate within 48 months to one-third the current size, with 50% of hearts for outpatient candidates, who would then have an 11% chance each month of receiving a heart compared with 0% if recent policies prevail. Total deaths, with and without transplantation, would be minimized by this rigorous selection of outpatient candidates. CONCLUSIONS: This study implies that immediate provisions should be made to limit candidate listing and revise expectations to reflect the diminishing likelihood of transplantation for outpatient candidates. Future emphasis should be on improved selection of candidates at highest risk without transplantation.

Continuing education in the physician's office: a pilot study for breast exams.

In response to a recent study indicating that primary care physicians were interested in receiving breast-screening education, an office-based training program was developed and delivered to fourteen physicians in Vermont and Florida. A nonphysician trainer and simulated patient provided instruction and feedback in clinical breast examination and in patient instruction in breast self-examination. Measurements of physician palpation skills before and after the training showed substantial skill improvement, and the office-based session was found to be highly acceptable by all participants.

Modeling distribution of donor hearts to maximize early candidate survival.

BACKGROUND: Priority for cardiac transplantation should reflect the relative waiting list mortality and operative mortality of outpatient candidates and critical candidates. METHODS AND RESULTS: To determine how to distribute donor hearts for maximal overall survival, a Markov model of eight states was constructed from current statistics for outpatient sudden death, deterioration to critical status, operative mortality for outpatients, and operative mortality for critical candidates. Because the fraction of hearts offered to critical candidates varied, expected survival at 1 year was calculated. To determine the factors most critical in determining priority policy, current conditions were then varied over a fourfold range. Priority for critical candidates maximized overall candidate survival (with and without transplantation), increasing 1-year survival to 78% compared with 66% if hearts were offered only to outpatients. The benefit of giving priority to critical patients persisted when current group mortality rates were individually halved or doubled because these rates were still small compared with the 100% expected mortality of critical patients without transplantation. If the outpatient sudden death rate and the operative mortality for critical patients were doubled simultaneously, however, there was a slight negative impact on survival if critical candidates received priority. Regardless of changes in subgroup outcomes, the distribution of donor hearts had a relatively modest impact on survival because of the large excess of candidates. CONCLUSIONS: Critical candidates for transplantation should continue to receive priority even if their operative mortality increases above current levels. However, postoperative outcomes must be assessed in relation to changing pretransplantation risks. Distribution of donor hearts will be most beneficial when it is possible to identify the waiting patients at greatest risk for sudden death and deterioration without transplantation.

A turnover prevention program for child care workers: a failed effort?

This study describes efforts to reduce turnover of child care workers, one of the many activities undertaken within the Milieu Enhancement Project. This 3-year endeavor, funded by the Division of Nursing of the Department of Health and Human Services, allowed nurses to provide care for orphaned and disadvantaged children, test the value of a nursing practice model, analyze the cost-benefit and the cost-effectiveness of the project, computerize existing and model-derived health care records, and allow faculty and graduate students to practice autonomously in a nontraditional setting. The research question was: What is causing job dissatisfaction in child care workers? Nurses and social workers used the Milieu Enhancement Model to conceptualize, address, and evaluate factors contributing to turnover. While statistical significance was not obtained in the turnover rates before and after implementation of the Turnover Prevention Program, the milieu was enhanced in many ways. Data are presented to support many aspects of the program's success.

Humor: a coping response for student nurses.

This qualitative study describes various situations that elicited a humorous coping response in student nurses assigned to a state psychiatric hospital. The research question asked was: Under what circumstances do student nurses choose to use humor as a coping method? Forty-three senior student nurses enrolled in a north-central United States university were invited to participate anonymously in the study. A content analysis of 38 narratives describing humorous situations was conducted and the emergent categories were evaluated for compatibility with Lazarus's theory of stress and coping. Novel and bizarre behaviors, novel and bizarre thoughts, negative evaluations of self and role, perceived threats to physical well-being, and wit were common antecedents fostering tension in the form of anxiety, frustration, fear, and puzzlement. Students used cognitive appraisal and humorous coping to mediate the stressful person-environment relations for positive outcomes. The cognitive and behavioral efforts to manage these emotions in a humorous manner were identified.

Freud and the mighty warrior.

This essay traces a prominent facet of Freud's personality, his being a "mighty warrior" throughout his life. This aspect of his character evolved as a reaction formation against his submissive father and as an identification with his more aggressive mother. He first tried it out in his highly ambivalent relationship to his nephew John, who was one year older. In his childhood play, Freud identified with certain military heroes, such mighty warriors as Napoleon, Hannibal, Alexander the Great, and Massena. As he grew older he shifted from military heroes to other great men including Goethe, Shakespeare, and finally Moses. He substituted these men as ego ideals in place of his father about whose stature he felt disillusioned. He far surpassed his father in his life achievements and yet managed to maintain an even-handed, respectable relationship with him until he died in 1896. His mother all but worshipped Sigmund but also demanded that he achieved the maximum in whatever he did. He had to earn her love by an outstanding performance but always wanted to feel unconditionally loved. His mighty warrior attitude developed into an important part of its personality. It protected him from feelings of helplessness and inadequacy and made him into an outstanding leader of the psychoanalytic movement.

Princess Marie Bonaparte, Edgar Allan Poe, and psychobiography.

Princess Marie Bonaparte was a colorful yet mysterious member of Freud's inner circle of psychoanalysis. In analysis with Freud beginning in 1925 (she was then 45 years old), she became a lay analyst and writer of many papers and books. Her most ambitious task was a 700-page psychobiography of Edgar Allan Poe that was first published in French in 1933. She was fascinated by Poe's gothic stories--with the return to life of dead persons and the eerie, unexpected turns of events. Her fascination with Poe can be traced to the similarity of their early traumatic life experiences. Bonaparte had lost her mother a month after her birth. Poe's father deserted the family when Edgar was two years old, and his mother died of tuberculosis when he was three. Poe's stories helped him to accommodate to these early traumatic losses. Bonaparte vicariously shared in Poe's loss and the fantasies of the return of the deceased parent in his stories. She was sensitive and empathetic to Poe's inner world because her inner world was similar. The result of this psychological fit between Poe and Bonaparte was her psychobiography, The Life and Works of Edgar Allan Poe. It was a milestone in psychobiography but limited in its psychological scope by its strong emphasis on early childhood trauma. Nevertheless it proved Bonaparte a bona fide creative psychoanalyst and not a dilettante propped up by her friendship with Freud.

Psychoanalytic understanding and treatment of the very rich.

Because personal affluence and an alloplastic adjustment tend to go together, psychiatric treatment encounters special problems in trying to help the very rich. These patients frequently show a strong sense of entitlement and a denial of any psychological problem. This creates special treatment problems. They feel entitled to the "very best," which includes the "best doctor." If their psychological problems cannot be magically erased they will switch psychiatrists until they find the "right one." Part of this is a tendency to externalize their emotional problems. Problems are thought to be caused by the environment and not by intra-psychic conflicts. This encourages the therapist to make environmental changes to improve the psychological state. Other special problems that the very rich present include the V.I.P. syndrome, excessive concern with litigation, their excessive narcissim, and their original emotional neglect by their own parents. Many were raised by parent surrogates and have problems in self-esteem. All of these special problems make the very rich difficult to treat with psychodynamically oriented psychotherapy or psychoanalysis. There are some exceptions to this problematic picture in which psychiatric treatment of the very rich can work out very nicely for both patient and psychotherapist.

Freud's antipathy to America.

Freud first saw this in America's attitude toward the use of cocaine. It was freely and legally used and even promoted by American physicians as beneficial in many medical conditions. Freud was first swept along by America's prococaine enthusiasm. He narrowly missed destroying his own medical reputation by his continuing close connection and advocacy of cocaine. Freud made his only visit to America in 1909. Despite the success of his visit and the congeniality of Americans toward him, he was already programmed toward a negative response. He allowed minor everyday inconveniences and cultural differences to spoil the trip for him. The chronic intestinal distress that had bothered him previously now was labelled as his "American dyspepsia." He developed additional reasons for disliking America. They accepted his three key dissenters, Adler, Jung, and Rank. He even believed that these three men achieved greater notoriety and popularity in America than he did. In fact, the Freudian psychoanalytic movement became much larger and more powerful in America than did the followings of any or all of his defectors. Freud did not like the shortcuts and lack of mastery of the basics of psychoanalysis that he believed happened in America. Some of this was true, but it was mainly exaggerated in Freud's mind. The gold of psychoanalysis was never transformed into a practical but deficient psychoanalytic alloy as Freud feared it might. There was a genuine disagreement about whether a psychoanalyst should have to become a medical doctor or not. It was a complicated issue in America because of laws that said that doing psychoanalysis was practicing medicine. Freud viewed the American stand against recognizing lay analysts as more evidence of American's being a rebellious son. Economic factors also played a significant factor in Freud's dislike of America. Freud was initially enthusiastic about President Wilson and his plans for peace. He found after World War I that all of his savings were wiped out and that Vienna suffered from a crippling inflation. As a result of this he had to take increasingly more American analysands as they paid him in valuable American dollars. He resented this financial dependency on Americans. He also had difficulty communicating with these American analysands and largely blamed them for their undisciplined way of speaking. What I have presented is a survey or overview of the reasons for Freud's dislike of America.(ABSTRACT TRUNCATED AT 400 WORDS)

Physician interest in breast cancer screening education. A survey of Vermont family physicians.

A mailed survey of 141 Vermont family physicians (74% participating) was conducted to determine their breast cancer screening practices and beliefs and their interest in receiving training in breast cancer screening. Of these, only 12% reported that at least three fourths of their female patients older than 50 years received mammograms at least once a year, compared with 33% who reported providing breast self-examination instruction and 35% who administered clinical breast examination with at least three fourths of these patients at least once a year. Nevertheless, 55% of the physicians rated mammography as a very effective breast-screening procedure; 28% rated breast self-examination and 16% rated clinical breast examination as very effective. Three fourths of the physicians showed great interest in learning more about breast palpation, breast self-examination instruction, and mammography. Individual instruction in the office was preferred over a group workshop format, and a trained nonphysician health professional was considered as acceptable as a physician to provide the instruction. Results suggest that breast cancer screening education for family physicians is a high priority, and that physicians will welcome such training, particularly if it is office-based.

Sigmund Freud and money.

I have tried to clarify Sigmund Freud's attitude toward money during the different time periods of his life. Most biographers have written that Freud was born into a poor family that later was elevated to the socioeconomic middle class in Vienna. This traditional viewpoint can be supported by various of Freud's letters and writings. A very different viewpoint has been proposed by the well-known American economist, Peter Drucker. As has been noted, his parents knew the Freud family in Vienna where Drucker actually met Freud. Drucker contends that Freud unconsciously misrepresented his parents' financial situation by creating the myth that they lived in poverty. Furthermore, Freud also developed another myth that it was because of the strong anti-Semitism in Vienna that he was so delayed in being appointed a professor of psychiatry. Drucker points out that the majority of the Viennese physicians were Jewish and that Freud's becoming a professor did not entail a delay and was not affected by any anti-Semitism in Vienna. Another area of conflict between Freud and the other Viennese physicians was Freud's refusal to treat any of his psychoanalytic patients without a fee. Freud believed that treating a patient in analysis for free created a transference-countertransference problem that might doom the treatment to failure. Freud's transference explanation for not taking on charity patients did not satisfy many of his Viennese physician colleagues. They believed that Freud was given an opportunity to accept their traditional standards and turned it down. In their eyes, Freud rejected them, they did not reject him. The same reasoning applied to the Viennese physicians' request for some scientific proof of the efficacy of psychoanalysis. Freud could only provide them with anecdotal or testimonial evidence to support psychoanalytic treatment. This placed psychoanalysis in the category of a belief system and not a scientific treatment. Drucker explains Freud's "obsession" with having lived in poverty as a manifestation of his "poorhouse neurosis." According to Drucker this syndrome was frequently found among Viennese during the last quarter of the 19th century. It was an irrational and deep-seated fear that an individual and his family were on the verge of being placed in the poorhouse because they lacked any funds. Freud does not specifically mention his having this irrational fear or obsession, but he made several statements quoted here indicating such a dread. At a recent psychoanalytic meeting I asked Freud scholar John Gedo of Chicago if he thought Freud experienced a "poorhouse neurosis."(ABSTRACT TRUNCATED AT 400 WORDS)