Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia.

Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBFB-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RISs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Plagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia.

Vital signs for your cardiovascular services.

Current trends and "best practice" operating statistics can be vital to the success of today's cardiovascular programs. The findings from a recently published survey entitled, "Trends in Cardiovascular Programs: A National Benchmarking Study", provide the administrator with immediate and current knowledge of best ways to manage cardiovascular services to succeed in a competitive market. Study results provide some interesting and valuable information regarding non-invasive cardiology, cardiac catheterization, and peripheral vascular angiography program administration and provide insight into issues of cost, quality, and cardiovascular program concerns, interests and needs.

Vascular delay and administration of basic fibroblast growth factor augment latissimus dorsi muscle flap perfusion and function.

Ischemia of the distal latissimus dorsi muscle flap occurs when the entire muscle is acutely elevated. Although this level of ischemia may not be critical if the muscle is to be used as a conventional muscle flap, the ischemia causes decreased distal muscle function if it is used for dynamic muscle flap transfer. This experiment was designed to determine whether or not the administration of exogenous basic fibroblast growth factor (bFGF), combined with a sublethal ischemic insult (i.e., vascular delay), would further augment muscle perfusion and function. Both latissimus dorsi muscles of nine canines were subjected to a bipedicle vascular delay procedure immediately followed by thoracodorsal intraarterial injection of 100 microg of bFGF on one side and by intraarterial injection of vehicle on the other. Ten days later, both latissimus dorsi muscles were raised as thoracodorsally based island flaps, with perfusion determined by laser-Doppler fluximetry. The muscles were wrapped around silicone chambers, simulating cardiomyoplasty, and stimulating electrodes were placed around each thoracodorsal nerve. The muscles were then subjected to an experimental protocol to determine muscle contractile function. At the end of the experiment, latissimus dorsi muscle biopsies were obtained for measurement of bFGF expression. The results demonstrated that the administration of 100 microg of bFGF immediately after the vascular delay procedure increases expression of native bFGF. In the distal and middle muscle segments, it also significantly increased muscle perfusion by approximately 20 percent and fatigue resistance by approximately 300 percent. The administration of growth factors may serve as an important adjuvant to surgical procedures using dynamic muscle flap transfers.

Muscular urinary sphincter: electrically stimulated myoplasty for functional sphincter reconstruction.

PURPOSE: To reconstruct an electrically stimulated muscular urinary sphincter (MUS) using a tailored gracilis muscle free flap with intact nerve. MATERIALS AND METHODS: Unilateral surgically tailored gracilis muscle free flaps were transferred into the pelvis in eight dogs, leaving the obturator nerve intact. The muscle's pedicle vessels were anastomosed to the inferior epigastric artery and vein in the pelvis and the muscle was wrapped around the bladder neck. Electrodes were inserted into the MUS and connected to a programmable pulse generator. After 8 weeks of training the MUS, the pulse generator was programmed to be "on" for 4 hours and "off' for 15 minutes in a continuous cycle. Urodynamic studies were performed periodically, and at the end of the experiment the MUS and proximal urethra were harvested for histology. Three control dogs had sham operations. RESULTS: All MUS's functioned well following the procedure. Histology of the MUS/urethra complex showed no evidence of stricture. Except for one dog, all urethras were easily catheterized. CONCLUSIONS: This electrically stimulated innervated free-flap MUS technique effectively increases bladder outlet resistance without producing urethral obstruction.

Electrically stimulated free-flap graciloplasty for urinary sphincter reconstruction: a new surgical procedure.

In electrically stimulated (dynamic) graciloplasty for urinary incontinence, the gracilis muscle is transposed into the pelvis, and the distal part is used to reconstruct a neosphincter. Clinical outcomes using this technique have been disappointing due to stricture of the urethra caused by ischemia in the distal part of the gracilis and limited gracilis length available for neosphincter construction. Furthermore, the urethra is twisted by the contracting gracilis, rather than circumferentially squeezed. The purpose of the present study was to test the anatomical and functional feasibility of a new surgical approach to reconstruct a urinary sphincter, using the gracilis muscle as a free flap. In 12 human cadavers, the anatomical feasibility for creating a neosphincter by using the gracilis free flap was determined. In all cases, transfer of the gracilis muscle into the pelvis as a free flap (with the nerve intact) was feasible, and ample muscle was available to construct a neosphincter around the bladder neck. Gracilis neosphincter function was studied in seven dogs. The left gracilis muscle was subjected to transfer into the pelvis as an innervated free flap to create a neosphincter around the urethra. The right (control) gracilis muscle was lifted as a single pedicle flap, remained in situ, and was wrapped around a stent to mimic the urethra. Function (expressed as peak pressure generation and fatigue rate) and surface perfusion were determined for all gracilis muscles. In each dog, both sides were compared using the paired Student's t test for statistical analysis, and no significant difference was measured for the two groups. In conclusion, an innervated gracilis free flap can be used to create a neosphincter around the bladder neck. In an acute study in dogs, function and perfusion of the innervated gracilis free flap are not compromised.

Vascular delay of the latissimus dorsi muscle: an essential component of cardiomyoplasty.

BACKGROUND: Cardiomyoplasty (CMP) uses the latissimus dorsi muscle (LDM) to assist the heart in cases of cardiac failure. Distal ischemia and necrosis of the LDM is a recognized complication of CMP that can reduce distal muscle function and the mechanical effectiveness of CMP. METHODS: Canine (n = 9) LDMs were subjected to a 10-day period of vascular delay followed by a simulated CMP. Two weeks after simulated CMP (corresponding to the healing delay between CMP and the onset of LDM stimulation used in the clinical setting), LDM perfusion was measured in the distal, middle, and proximal segments of the muscle, and circumferential (distal and middle squeezing muscle function) and longitudinal (proximal pulling muscle function) force generation and fatigue rates were measured. The results were compared with the contralateral nondelayed simulated CMP. RESULTS: Muscle perfusion was significantly (p < 0.05) greater in the distal and middle segments of vascular-delayed LDMs. Circumferential muscle force generation and fatigue rates were significantly (p < 0.05) improved in the vascular-delayed LDMs. CONCLUSIONS: Vascular delay can significantly improve LDM perfusion and function in a model that closely reflects clinical CMP, and the use of vascular delay may improve clinical outcomes in CMP.

Vascular delay improves latissimus dorsi muscle perfusion and muscle function for use in cardiomyoplasty.

Ischemia of the distal portion of the latissimus dorsi muscle occurs in muscle transfer for cardiomyoplasty and reduces distal muscle contractility and thus the mechanical effectiveness of cardiomyoplasty. We hypothesized that muscle function would be improved by a vascular delay procedure that increases distal muscle perfusion of the latissimus dorsi muscle. The latissimus dorsi muscles of 10 adult mongrel dogs were subjected to a vascular delay procedure on one side and a sham procedure on the other. Following 10 days of vascular delay, muscle perfusion was measured with a laser-Doppler perfusion imager before and after elevation of the muscles as flaps based only on their thoracodorsal neurovascular pedicles. The muscles were wrapped and sutured around silicone chambers (simulating cardiomyoplasty), a stimulating electrode was placed around each thoracodorsal nerve, and the muscles were stimulated to contract in both rhythmic and tetanic fashion. Circumferential (distal and middle latissimus dorsi muscle function) force generation and fatigue rates were measured independently. Circumferential muscle force, circumferential and longitudinal fatigue rate, and distal, middle, and overall perfusion were significantly (p < 0.05) improved in delayed muscle compared with nondelayed muscle. We found that a vascular delay procedure and a 10-day delay adaptation period significantly improve latissimus dorsi muscle flap perfusion and function, particularly in the distal and middle portions of the muscle. Delay should be considered as a means of improving the clinical outcome in cardiomyoplasty.

Value-sensitive therapy: learning from ultra-orthodox patients.

This paper explores the issues that arise when psychotherapists and patients do not share a common value system. Using three case studies of ultra-Orthodox Jewish patients who hold religious values and beliefs, the paper illustrataes and defines a strategy of "value-sensitive therapy." It argues for treating patients without demeaning or discounting their values and beliefs.

Patients, chaperons and healers: enlarging the therapeutic encounter.

The common assumption in most therapy is that the process is initiated by a need in the patient and managed or directed by the therapist. If there are other people involved, except for the case of group or family therapy, they are at best marginal to the ongoing process as conducted in the therapy room. This paper, jointly written by a social anthropologist and psychiatrist, presents a model of therapy in an ultra-Orthodox Jewish community in which chaperons accompanying the patient (a common feature in the setting) may fulfil important functions as cultural bridges, sometimes even going so far as serving as active co-therapists. Ethnographic data is offered to demonstrate how chaperons may assist in enabling the healers to overcome feelings of 'cultural distress' and discomfiture on the part of the patients and how they assist the therapists to be 'culturally sensitive' in their use of psychiatric methods in a population which has deep misgivings about such procedures. The paper concludes with an argument for increased openness and flexibility in the practice of psycho-therapy, particularly in cross-cultural encounters, which would allow for greater use of chaperons.