Increased incidence and mortality associated with skin cancers after cardiac transplant.

Skin cancer incidence has been shown to be increased in the context of transplant-associated immunosuppression. There is, however, limited information specifically about the incidence of skin cancer after cardiac transplantation in the United States. A 10-year retrospective cohort study of 6271 heart transplants at 32 US transplant centers revealed increased postprocedure incidence of nonmelanoma and melanoma skin cancers, especially cutaneous squamous cell carcinoma, for which the incidence increased from 4- to 30-fold compared to the age and gender equivalent general population. Incidence of skin cancer in this study was consistent with prior single-center data regarding cardiac transplant patients. Comparison of all-cause mortality statistics for patients with basal cell carcinoma, squamous cell carcinoma and melanoma, respectively, demonstrated increased mortality associated with melanoma. Skin cancer screening and prophylaxis may be of some utility in reducing morbidity and mortality in cardiac transplant patients.

G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation.

G protein-coupled receptors (GPCRs) transduce extracellular signals into intracellular events. The waning responsiveness of GPCRs in the face of persistent agonist stimulation, or desensitization, is a necessary event that ensures physiological homeostasis. GPCR kinases (GRKs) are important regulators of GPCR desensitization. GRK5, one member of the GRK family, desensitizes central M(2) muscarinic receptors in mice. We questioned whether GRK5 might also be an important regulator of peripheral muscarinic receptor responsiveness in the cardiopulmonary system. Specifically, we wanted to determine the role of GRK5 in regulating muscarinic receptor-mediated control of airway smooth muscle tone or regulation of cholinergic-induced bradycardia. Tracheal pressure, heart rate, and tracheal smooth muscle tension were measured in mice having a targeted deletion of the GRK5 gene (GRK5(-/-)) and littermate wild-type (WT) control mice. Both in vivo and in vitro results showed that the airway contractile response to a muscarinic receptor agonist was not different between GRK5(-/-) and WT mice. However, the relaxation component of bilateral vagal stimulation and the airway smooth muscle relaxation resulting from beta(2)-adrenergic receptor activation were diminished in GRK5(-/-) mice. These data suggest that M(2) muscarinic receptor-mediated opposition of airway smooth muscle relaxation is regulated by GRK5 and is, therefore, excessive in GRK5(-/-) mice. In addition, this study shows that GRK5 regulates pulmonary responses in a tissue- and receptor-specific manner but does not regulate peripheral cardiac muscarinic receptors. GRK5 regulation of airway responses may have implications in obstructive airway diseases such as asthma or chronic obstructive pulmonary disease.

CD3 monitoring and thymoglobulin therapy in cardiac transplantation: clinical outcomes and pharmacoeconomic implications.

INTRODUCTION: CD3 monitoring of antithymocyte globulin therapy in renal transplantation has been shown to be more cost-effective than standard regimens. The objective of this study was to evaluate CD3 monitoring with Thymoglobulin in cardiac transplantation. METHODS: Cardiac transplant patients who required antithymocyte globulin therapy were dose-adjusted to maintain absolute CD3 counts <25 cells/microL. Endomyocardial biopsies and hemodynamic parameters were used to assess efficacy. The incidences of hematological side effects, opportunistic infections, and malignancies were recorded; in addition we performed a cost comparison. RESULTS: Eight patients were treated with Thymoglobulin using CD3 monitoring to adjust the dosing. All patients responded with few side effects. Compared to standard dosing, CD3 monitoring allowed a 60% reduction in the average total dose and a 58% reduction in cost per patient. CONCLUSION: CD3 monitoring of Thymoglobulin therapy in cardiac transplant patients results in lower doses and reduced costs with equivalent efficacy and a low incidence of complications.

Subfascial implantation of intrathecal baclofen pumps in children: technical note.

OBJECTIVE: Indwelling intrathecal drug delivery systems are becoming increasingly important as a method of neuromodulation within the nervous system. In particular, intrathecal baclofen therapy has shown efficacy and safety in the management of spasticity and dystonia in children. The most common complications leading to explantation of the pumps are skin breakdown and infection at the pump implantation site. The pediatric population poses particular challenges with regard to these complications because appropriate candidates for intrathecal baclofen therapy are often undernourished and thus have a dearth of soft tissue mass to cover a subcutaneously implanted baclofen pump. We report a technique of subfascial implantation that provides greater soft tissue coverage of the pump, thereby reducing the potential for skin breakdown and improving the cosmetic appearance of the implantation site. METHODS: Eighteen consecutively treated children (average age, 8 yr, 7 mo) with spasticity and/or dystonia underwent subfascial implantation of a baclofen pump. These children's mean weight of 42.9 lb is less than the expected weight for a group of children in this age group, ranging from 4 years, 8 months, to 15 years, 7 months. In all patients, the pump was inserted into a pocket surgically constructed between the rectus abdominus and the external oblique muscles and the respective anterior fascial layers. RESULTS: At an average follow-up of 13.7 months, no infection or skin breakdown had occurred at the pump surgical site in any of the 18 patients. CONCLUSION: At this early follow-up, the subfascial implantation technique was associated with a reduced rate of local wound and pump infections and provided optimal cosmetic results as compared with that observed in retrospective cases.

Modification of fibrinogen with poly(ethylene glycol) and its effects on fibrin clot characteristics.

The suitability of existing topical fibrin glue preparations for tissue sealing or local drug delivery applications is greatly limited by their poor mechanical properties and the limited capacity of fibrinogen (Fgn) to actively bind growth factors or other therapeutic agents. Poly(ethylene glycol) (PEG) offers potential solutions to these problems by providing a mechanism for increasing the number of crosslinks between adjacent fibrin monomer molecules or for covalently crosslinking Fgn to therapeutic agents. The feasibility of this approach requires the full biological activity, or clottability, of PE glycolated Fgn. This study characterizes the clot characteristics of Fgn modified to varying degrees with monofunctional succinimidyl propionate PEG (5000 Da). The data indicate that, although thrombin clotting times are significantly altered, Fgn maintains 90% of its capacity to clot upon the addition of up to 5 PEG/Fgn. Further derivatization significantly decreases the Fgn clottability. The addition of up to 5 PEG/Fgn has little, if any, effect on the kinetics of degradation by plasmin. The results suggest that limited modification of Fgn with lysine-reactive PEG allows therapeutic enhancement of fibrin glues.

Hip arthrodesis in adolescents using external fixation.

Between 1994 and 1998, seven adolescents underwent hip arthrodesis with the use of an external fixator. Mean time of follow-up was 24.0 months after surgery. The duration of fixation and time to fusion were 6.6 months (range, 5-9.5 months) and 8.0 months (range, 5.2-15 months), respectively. At most recent follow-up, there was a significant improvement in the mean modified Harris hip score, in which the maximum score is 91 points after omitting 9 points for hip range of motion and deformity, from 25.7 before surgery to 66.7 after surgery (p < 0.01). The advantages of this procedure include (i) the ease and accuracy of obtaining the proper position for fusion, (ii) the ability to lengthen the affected leg at the same time, (iii) the diminished likelihood of compromising future hip operations, and (iv) the ability to ambulate and bear weight throughout the treatment course. We recommend this method of hip arthrodesis with external fixation for patients with intractable hip pain necessitating this procedure.

The use of bone scan to investigate back pain in children and adolescents.

Children with back pain frequently undergo detailed investigation because of the perception that a high percentage will have a treatable spinal condition. The purposes of this study was (i) to determine the percentage of children with disabling back pain presenting to our institution who had a diagnosis (i.e., to explain their back pain), (ii) to evaluate the clinical markers that should alert clinicians to underlying pathology, (iii) and to determine the prognosis of children with back pain and no specific diagnosis. This study was a retrospective analysis of consecutive children undergoing single-photon emission computed tomography for a primary complaint of back pain. Data collection included chart review, radiographic analysis, and clinical follow-up with the Roland and Morris scale for pain and disability. Two hundred and seventeen patients with an average age of 13 years (range, 2.7-17.7) were reviewed on average 4.4 years after presentation (range, 1.1-7.2 years). One hundred and seventy children (78.3%) had no specific diagnosis to explain their back pain, 15 children (6.9%) had spondylosis, 10 children (4.6%) had tumor, and the remaining 22 children (10.1%) had various diagnoses including infection, Scheuermann's kyphosis, herniated disc, kidney disease, facet arthritis, degenerative disc disease, congenital anomalies, and tethered cord. Factors associated with positive diagnoses were constant pain and male gender. Night pain, constant pain, and duration of symptoms <3 months were associated with the diagnosis of a tumor. Although the majority of children presenting with persistent back pain had no demonstrable cause, of 132 contactable patients 94 (71%) had persisting pain at the time of clinical follow-up. In conclusion, the majority of children with disabling back pain has no demonstrable cause and the majority will continue to have pain years after initial presentation.

Modulation of mechanical properties in multiple-component tissue adhesives.

In vitro, ex vivo, and in vivo studies were performed to investigate the effect of mixing upon the mechanical properties of a two-component tissue adhesive. The hypothesis investigated was that a more complete mixing of the two components would yield an increase in the mechanical performance of the adhesive. This in turn would be demonstrated by improved outcomes in models of clinical sealant application. In vitro stereological analysis of tissue adhesive mixed and delivered by several different applicators demonstrated variation in the amount of mixing provided by each type of delivery system. Ex vivo tensile adhesive strength showed that there was a correlation between the amount of mixing and bonding strength; that is, more thorough mixing demonstrated higher adhesive strength. No significant difference was seen, however, between the different applicator types and impact on in vivo dermal incisional closure strength. There was a correlation, though, in amount of mixing and in vivo hemostasis. In a rabbit spleen incision model, a more thoroughly mixed sealant corresponded with a decrease in time to obtain complete hemostasis, as well as less sealant used. The effects of mixing on tissue-adhesive mechanical performance were influenced somewhat by the amount of mixing provided by the applicator. This effect, however, was dependent upon the sealant formulation and the type of in vivo application.

Congenital pseudoarthrosis of the tibia.

Congenital pseudoarthrosis of the tibia remains one of the most difficult conditions to treat in orthopedic surgery. Seven cases were treated in our hospital by different methods. Three out of seven patients were healed, two of these refractured. At follow-up, the success rate was 14% (one out of seven cases). It is our recommendation that early primary amputation with an appropriate prosthesis should be considered, and that the final evaluation should not be based on obtaining bone union, but on the level of function of the lower extremity.

Fibrin scaffold as an effective vehicle for the delivery of acidic fibroblast growth factor (FGF-1).

The effect of wound healing by fibrin and acidic fibroblast growth factor (FGF-1) in an in vivo model was evaluated in this study. Four full-thickness wounds were made on the dorsum of each rabbit (n = 5). Each of these wounds had different treatment groups: control, topical FGF-1 (100 microg/9 cm2), fibrin (2.0 mL at 60 mg/mL fibrinogen), and FGF-1 (100 microg/9 cm2)/fibrin. The animals were sacrificed at the end of 2 weeks. Histomorphometric analysis and mechanical testing were conducted to assess the healing response. FGF-1/fibrin treatment improved the mechanical properties of the healed tissue. Fibrin scaffold exhibited the desired tissue response, as demonstrated by the lack of inflammation, and was deemed an effective carrier for FGF-1.

The effect of solvent extraction and sterilization procedure on the tissue response to Dacron velour.

The effects of solvent extraction and sterilization procedure on tissue response to Dacron velour were studied in a canine model, using histomorphometrical techniques. The solvents used for extraction of low molecular weight moieties were either ethanol or water: the sterilization techniques examined were ethylene oxide (ETO) treatment, steam sterilization, and radiofrequency glow discharge (RFGD) treatment. The effect of the sterilization procedure was most marked in the outermost regions (velour) of the implant; no sterilization effects were determined in the capsule or the knitted regions. Velour in the steam sterilized implants had the smallest blood vessel dimensions compared with those that were treated with ETO or RFGD. The effects of different extraction methodologies appeared to be more significant than sterilization effects and were detected further into the implant. That is, not only were extraction effects detected in the capsule and velour, they were also detected in the outer knitted region. Extraction with water resulted in histological responses considered more biologically desirable (thinner capsule, lower giant cell presence, and larger blood vessel diameters) than responses to extraction with ethanol. Neither extraction nor sterilization effects were detected in the inner layers of the knitted region, which were adjacent to the adhesive.

Effects of managed care on physician-patient relationships, quality of care, and the ethical practice of medicine: a physician survey.

BACKGROUND: Survey studies have shown that physicians believe managed care is having significant impact on many of their professional obligations. METHODS: Primary care physicians were asked about the impact of managed care on: (1) physician-patient relationships, (2) the ability of physicians to carry out their professional ethical obligations, and (3) quality of patient care. In 1996 we surveyed 1011 primary care physicians in Pennsylvania. The survey group's responses were graded on a Likert scale. Space was provided for respondents to include written comments. The SPSS statistical software (SPSS Inc, Chicago, Ill) was used to analyze the data. RESULTS: The response rate was 55%. Most respondents indicated that under managed care physicians are less able to avoid conflicts of interest and less able to place the best interests of patients first. The majority responded that quality of health care is compromised by limitations in location of diagnostic tests, length of hospital stay, and choice of specialists. A significant minority (27%-49%) noted a decrease in the physician's ability to carry out ethical obligations, to respect patient autonomy, and to respect confidentiality in physician-patient communication. Most physicians expressed that managed care made no impact on ability to obtain informed consent or to provide information. There were small but statistically significant sex differences, with female physicians more negative toward managed care. CONCLUSIONS: Many physicians surveyed believe managed care has significant negative effects on the physician-patient relationship, the ability to carry out ethical obligations, and on quality of patient care. These results have implications for health care system reform efforts.

Stimulation of angiogenesis by FGF-1 delivered through a modified fibrin scaffold.

A few studies have indicated that repeated dosing of acidic fibroblast growth factor (FGF-1) is essential to be effective in modulating the wound-healing response. However, little investigation has been done to determine the effective dosing regimen of FGF-1 or the appropriate carrier vehicle for this growth factor. The main objective of this study was to determine the effective angiogenic stimulatatory dose of FGF-1 delivered through a modified fibrin matrix, using a rabbit ear ulcer model. Specifically, the aim was to test the effects of FGF-1 on the angiogenic, fibroblastic, and epithelial responses in a wound model. Five 6-mm diameter ulcers to the depth of bare cartilage were created on each rabbit ear. Four different combinations (0.8, 8, 80, and 800 micrograms/ml) of the growth factor were examined across two periods of study. Pooled modified fibrin was used to deliver the growth factor. Histomorphometrical quantification was conducted after routine histological processing of the ulcers sites. Data analysis indicated a strong correlation between concentration and the histomorphometric response. In general, the growth factor treatments affected the healing response and exhibited a dose-dependent behavior. The addition of FGF-1 led to an increase in the angiogenic and fibroblastic responses, as well as an increase in the epithelialization rate. The preferred dose of 8 micrograms initiated a high epithelialization rate, fibroblastic, and angiogenic responses, and was the lowest dose required to initiate these responses.

In vivo wound healing response to a modified degradable fibrin scaffold.

Pooled donor fibrin with an ultimate fibrinogen concentration of 60 mg/ml was used to study its effect on wound healing of surgically created ulcers in a rabbit ear. Water soluble polymer (PEG Mw = 20 KD) beads of 100-150 microns were added (12% by volume) to the fibrinogen to obtain a porous and rough structure. Five 6 mm-diameter ulcers to the depth of bare cartilage were created on each rabbit ear. There were two periods of study (4 and 8 days), with 15 ulcers in each time period, 5 of which were treated with a modified fibrin scaffold, 5 with a non-modified fibrin scaffold, and 5 served as control ulcers. The ulcer sites were subjected to routine histological processing and histomorphometrical quantification. Data analysis revealed significant increases in volume fraction of fibroblast and number of blood vessels in the modified fibrin scaffold treated ulcers over control and non-modified fibrin scaffold treated groups.

Spinal muscarinic, glutamatergic and GABAergic receptor systems in cardiovascular regulation.

The central administration of cholinergic agonists can produce a significant increase in arterial blood pressure by enhancing sympathetic vasomotor tone. The stimulation of spinal muscarinic receptors through intrathecal (i.t.) injection of carbachol in rats evoked a significant pressor response that returned to preinjection levels within 30 to 40 min. We investigated the roles of glutamatergic and GABAergic receptors in mediating the hypertensive response to i.t. injection of the muscarinic receptor agonist carbachol and in the maintenance of resting blood pressure and heart rate. The i.t. pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonists D-AP7 or MK801 maleate (dizocilipine) attenuated the pressor response to i.t. administration carbachol in a dose-dependent manner in conscious, freely moving rats. In contrast, i.t. pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione, a non-NMDA glutamate receptor antagonist, was not effective in this regard, indicating that the carbachol-evoked pressor response was not mediated through the quisqualate/kainate subtype of glutamate receptors. The i.t. pretreatment with the gamma-aminobutyric acid type B receptor agonist baclofen also inhibited the pressor response to i.t. injection of carbachol at doses that did not alter motor function. To determine whether the pressor response to stimulation of spinal muscarinic receptors required the participation of higher centers, rats received an intracisternal injection of either methylatropine or D-AP7 before the i.t. injection of carbachol. Both intracisternal pretreatments significantly reduced the expression of the pressor response to i.t. injection of carbachol. These findings are consistent with the presence of a powerful modulating spinobulbar muscarinic pressor system. Pharmacological activation of this system involves the participation of spinal and perhaps medullary glutamate-NMDA and gamma-aminobutyric acid type B receptor systems.

Analysis of a biodegradable composite for bone healing.

A degradable L-PLA/calcium carbonate composite made of interconnecting phases was examined. This structure was used both to slow the degradation rate and to reduce the brittleness of the ceramic. Both in vitro and in vivo degradation studies were performed. Samples were incubated in buffered saline or placed in the dorsum of rats for 0, 1, or 4 weeks. Mechanical testing was performed on both groups, volume fraction of each component was determined for in vitro samples, and histology was performed on in vivo samples. Failure load, tensile strength, and elastic modulus significantly decreased during the 1st week for both groups. Continued decreases were seen at 4 weeks for in vitro samples but not for in vivo. Failure strain and tensile strength decreased only for in vitro specimens. PLA fraction significantly decreased during the 1st week and then stabilized. Histology showed that tissue ingrowth occurred at 4 weeks. The decrease in mechanical properties was probably a result of the decreased PLA fraction. The stabilization and even a slight increase in tensile strength and failure strain in the in vivo samples was probably due to the tissue ingrowth forming an implant-tissue composite.

Spinal muscarinic cholinergic and nitric oxide systems in cardiovascular regulation.

Pharmacological activation of muscarinic receptors located in the thoracic spinal cord evokes a marked increase in blood pressure and heart rate. We have previously demonstrated that the cardiovascular response to stimulation of spinal cord muscarinic cholinergic receptors is dependent upon a pharmacologically described ascending spino-bulbar pathway. The purpose of the study was to determine whether the blood pressure and heart rate responses to intrathecal (i.t.) injection of the muscarinic cholinergic receptor agonist carbachol are mediated by a local nitric oxide (NO)-generating system. Freely moving rats were previously prepared with chronic indwelling i.t. and intra-arterial catheters. Both the pressor and tachycardic responses produced by i.t. injection of carbachol were inhibited in a dose-dependent manner by i.t. pre-treatment with the NO synthase inhibitor N-omega-Nitro-L-arginine methylester (L-NAME). To confirm the site of action of the drugs employed in conscious rats, a separate group of rats was anesthetized, and using surgical procedures previously developed in this laboratory, drug distribution was limited specifically to the lower thoracic spinal cord. When carbachol was administered by i.t. injection and localized to the lower thoracic area, muscarinic cholinergic receptor stimulation again produced a marked pressor response, but without the accompanying tachycardia. The ability of N-omega-Nitro-L-arginine methylester (L-NAME) to inhibit the pressor response to carbachol in conscious rats was confirmed in anesthetized rats, although higher doses of L-NAME than those employed in conscious rats were required. L-NAME-induced inhibition of the carbachol-evoked pressor response was reversed by the L-, but not the D-isomer, of arginine. Moreover, i.t. pre-treatment with Methylene blue, that interferes with NO production and function, effectively inhibited the expression of the pressor response to i.t. injection of carbachol. The 'anti-muscarinic' action of L-NAME was not due to a direct interaction with spinal muscarinic receptors, as L-NAME did not significantly displace [3H]methyl-scopolamine from spinal cord membranes in vitro. The results of this study support the hypothesis that spinal muscarinic cholinergic receptors participate in a sympathoexcitatory pathway that interacts either directly or indirectly with a local NO-generating system involved in the regulation of blood pressure.

Fracture-dislocation of the neck of the talus in a ten-year-old child: a case report and review of the literature.

A ten-year-old female underwent open reduction and internal fixation of a Hawkins type III fracture of the talar neck. The fracture united within three months. However, avascular necrosis of the body of the talus occurred. Partial collapse of the talar body ensued despite protection from weight-bearing for eight months after surgery. This case illustrates that fracture-dislocation of the talus can occur in a child and has a guarded prognosis.