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1.
Plast Reconstr Surg ; 2023 Jul 18.
Article in English | MEDLINE | ID: mdl-37467120

ABSTRACT

SUMMARY: As volume and understanding of genital gender affirming surgery (gGAS) has grown, so has the spectrum of surgical techniques to better serve a wider range of transgender and non-binary individuals. Given the diverse spectrum of individuals seeking phalloplasty, we emphasize the importance of patient driven decision-making, beginning with the initial consultation. Phalloplasty surgery is not a one-size-fits-all surgery, but instead should be viewed from an individually-customized approach. This article discusses the technical details for vaginal preservation without scrotoplasty or clitoral tissue burial in a shaft-only phalloplasty (SOP). The technique involves degloving the clitoral shaft, with inset at the ventral base of the phallus, addressing the redundant clitoral hood, and accompanying reduction labiaplasty with a Y-to-V adjacent tissue transfer. The phallus may be neurotized with clitoral nerves from one side of the clitoris, and/or the ilioinguinal nerve. This technique obliterates the degloved clitoral hood and re-suspends the labia minora anteriorly, improving final aesthetics and striving to meet patient genital goals.

2.
Plast Reconstr Surg ; 150(3): 516e-525e, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35749739

ABSTRACT

BACKGROUND: No guidelines exist regarding management of breast tissue for transmasculine and gender-nonconforming individuals. This study aims to investigate the experiences and practices regarding perioperative breast cancer risk management among the American Society of Plastic Surgeons members performing chest masculinization surgery. METHODS: An anonymous, online, 19-question survey was sent to 2517 U.S.-based American Society of Plastic Surgeons members in October of 2019. RESULTS: A total of 69 responses were analyzed. High-volume surgeons were more likely from academic centers (OR, 4.88; 95 percent CI, 1.67 to 15.22; p = 0.005). Age older than 40 years [ n = 59 (85.5 percent)] and family history of breast cancer in first-degree relatives [ n = 47 (68.1 percent)] or family with a diagnosis before age 40 [ n = 49 (71.0 percent)] were the most common indications for preoperative imaging. Nineteen of the respondents (27.5 percent) routinely excise all macroscopic breast tissue, with 21 (30.4 percent) routinely leaving breast tissue. Fifty-one respondents (73.9 percent) routinely send specimens for pathologic analysis. There was no significant correlation between surgical volume or type of practice and odds of sending specimens for pathologic analysis. High patient costs and patient reluctance [ n = 27 (39.1 percent) and n = 24 (35.3 percent), respectively] were the most often cited barriers for sending specimens for pathologic analysis. Six respondents (8.7 percent) have found malignant or premalignant lesions in masculinizing breast specimens. CONCLUSIONS: Large variation was found among surgeons' perioperative management of chest masculinizing surgery patients regarding preoperative cancer screening, pathologic assessment of resected tissue, and postoperative cancer surveillance. Standardization of care and further studies are needed to document risk, incidence, and prevalence of breast cancer in the transmasculine population before and after surgery.


Subject(s)
Breast Neoplasms , Surgeons , Surgery, Plastic , Adult , Breast Neoplasms/surgery , Early Detection of Cancer , Female , Humans , Practice Patterns, Physicians' , Surveys and Questionnaires , United States
3.
J Reconstr Microsurg ; 38(5): 395-401, 2022 Jun.
Article in English | MEDLINE | ID: mdl-34428806

ABSTRACT

BACKGROUND: Unfractionated heparin infusions are commonly used in microvascular surgery to prevent microvascular thrombosis. Previously, fixed-dose heparin infusions were believed to provide sufficient venous thromboembolism (VTE) prophylaxis; however, we now know that this practice is inadequate for the majority of patients. Anti-factor Xa (aFXa) level is a measure of unfractionated heparin efficacy and safety. This study evaluated the pharmacodynamics of weight-based dose heparin infusions and the impacts of real-time aFXa-guided heparin dose adjustments. METHODS: This prospective clinical trial enrolled adult microvascular surgery patients who received a weight-based heparin dose following a microsurgical procedure. Steady-state aFXa levels were monitored, and patients with out-of-range levels received dose adjustments. The study outcomes assessed were aFXa levels at a dose of heparin 10 units/kg/hour, time to adequate aFXa level, number of dose adjustments required to reach in-range aFXa levels, and clinically relevant bleeding and VTE at 90 days. RESULTS: Twenty-one patients were prospectively recruited, and usable data were available for twenty patients. Four of twenty patients (20%) had adequate prophylaxis at a heparin dose of 10 units/kg/hour. Among patients who received dose adjustments and achieved in-range aFXa levels, the median number of dose adjustments was 2 and the median weight-based dose was 11 units/kg/hour. The percentage of patients with in-range levels was significantly increased (65 vs. 15%, p = 0.0002) as a result of real-time dose adjustments. The rate of VTE at 90 days was 0%, and clinically relevant bleeding rate at 90 days was 15%. CONCLUSION: Weight-based heparin infusions at a rate of 10 units/kg/hour provide a detectable level of anticoagulation for some patients following microsurgical procedures, but most patients require dose adjustment to ensure adequate VTE prophylaxis.


Subject(s)
Venous Thromboembolism , Adult , Anticoagulants/therapeutic use , Heparin , Humans , Microsurgery , Prospective Studies , Venous Thromboembolism/drug therapy , Venous Thromboembolism/prevention & control
4.
Fertil Steril ; 116(4): 924-930, 2021 10.
Article in English | MEDLINE | ID: mdl-34404544

ABSTRACT

Gender dysphoria, the discordance between one's gender identity and anatomy, affects nearly 25 million people worldwide, and the prevalence of transgender and non-binary identities is increasing because of greater acceptance and awareness. Because of the improved accessibility to gender-affirming surgery (GAS), many providers will care for patients during and after gender transition. For trans men (female-to-male), GAS represents a combination of procedures rather than a single surgery. The particular combination of masculinizing procedures is chosen on the basis of informed patient-provider discussions regarding the patient's goals and anatomy and implemented through a multidisciplinary team approach. In this review, we describe the common procedures comprising masculinizing GAS to improve delivery of specialized care for this patient population.


Subject(s)
Health Services for Transgender Persons , Sex Reassignment Procedures , Transgender Persons , Transsexualism/surgery , Urologic Surgical Procedures , Delivery of Health Care, Integrated , Female , Gender Dysphoria/psychology , Gender Identity , Humans , Male , Sex Reassignment Procedures/adverse effects , Time Factors , Transgender Persons/psychology , Transsexualism/physiopathology , Transsexualism/psychology , Treatment Outcome , Urologic Surgical Procedures/adverse effects
5.
Urology ; 152: 79-83, 2021 06.
Article in English | MEDLINE | ID: mdl-33493506

ABSTRACT

OBJECTIVE: To describe the infrapubic approach to penile prosthesis insertion in transmen after phalloplasty. MATERIALS AND METHODS: After verifying phalloplasty vascular pedicle anatomy and reliable micturition, patients may be considered for implant surgery. Specific modifications of the infrapubic approach to penile prosthesis insertion as well as individualization of commercially available implants are performed intraoperatively to help reduce the risk of postoperative complications. RESULTS: In our single surgeon series (MLC) using the infrapubic approach with these specific implants after phalloplasty, 17/107 (16%) patients from October 2017 to November 2020 required revision surgery after mean follow-up of 79.8 weeks. CONCLUSION: Our infrapubic prosthesis insertion after phalloplasty technique with modifications to commercially available implants may help reduce the risk of postoperative complications.


Subject(s)
Penile Implantation/methods , Penile Prosthesis , Sex Reassignment Surgery , Female , Humans , Male , Reoperation , Transgender Persons
6.
Ann Plast Surg ; 86(2): 129-131, 2021 02 01.
Article in English | MEDLINE | ID: mdl-33449461

ABSTRACT

ABSTRACT: As the detection of breast cancer in Ghana improves, the incidence of mastectomy has increased and the outcomes have improved. As a secondary result, the need for breast reconstruction is increasing. The cultural hesitation to undergo a mastectomy and live without a breast can be decreased by making breast reconstruction available, cost-effective, and acceptable. Cultural, economic, and technical factors were considered in choosing the best method of breast reconstruction. Discussions, lectures, and cadaver dissections investigated the various reconstructive options. Operative cases were performed using a latissimus musculocutaneous flap, a lower abdominal transverse rectus abdominis myocutaneous (TRAM) flap, and a midabdominal TRAM flap. The midabdominal TRAM was found to be the best choice at Komfo Anokye Teaching Hospital. It is a reliable, robust, well-perfused, single-stage flap that produced excellent patient satisfaction.


Subject(s)
Breast Neoplasms , Mammaplasty , Breast Neoplasms/surgery , Ghana , Hospitals, Teaching , Humans , Mastectomy , Needs Assessment , Rectus Abdominis/transplantation
7.
Transl Androl Urol ; 8(3): 209-218, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31380227

ABSTRACT

Transgender individuals who undergo gender-affirming medical or surgical therapies are at risk for infertility. Suppression of puberty with gonadotropin-releasing hormone agonist analogs (GnRHa) in the pediatric transgender patient can pause the maturation of germ cells, and thus, affect fertility potential. Testosterone therapy in transgender men can suppress ovulation and alter ovarian histology, while estrogen therapy in transgender women can lead to impaired spermatogenesis and testicular atrophy. The effect of hormone therapy on fertility is potentially reversible, but the extent is unclear. Gender-affirming surgery (GAS) that includes hysterectomy and oophorectomy in transmen or orchiectomy in transwomen results in permanent sterility. It is recommended that clinicians counsel transgender patients on fertility preservation (FP) options prior to initiation of gender-affirming therapy. Transmen can choose to undergo cryopreservation of oocytes or embryos, which requires hormonal stimulation for egg retrieval. Uterus preservation allows transmen to gestate if desired. For transwomen, the option for FP is cryopreservation of sperm either through masturbation or testicular sperm extraction. Experimental and future options may include cryopreservation and in vitro maturation of ovarian or testicular tissue, which could provide prepubertal transgender youth an option for FP since they lack mature gametes. Successful uterus transplantation with subsequent live birth is a new medical breakthrough for cisgender women with uterus factor infertility. Although it has not yet been performed in transgender women, uterus transplantation is a potential solution for those who wish to get pregnant. The transgender population faces many barriers to care, such as provider discrimination, lack of information, legal barriers, scarcity of fertility centers, financial burden, and emotional cost. Further research is necessary to investigate the feasibility of experimental FP options, provide better evidence-based information to clinicians and transgender patients alike, and to improve access to and quality of reproductive services for the transgender population.

9.
J Reconstr Microsurg ; 34(9): 729-734, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29788512

ABSTRACT

BACKGROUND: In microvascular surgery, patients often receive unfractionated heparin infusions to minimize risk for microvascular thrombosis. Patients who receive intravenous (IV) heparin are believed to have adequate prophylaxis against venous thromboembolism (VTE). Whether a fixed dose of IV heparin provides detectable levels of anticoagulation, or whether the "one size fits all" approach provides adequate prophylaxis against VTE remains unknown. This study examined the pharmacodynamics of fixed-dose heparin infusions and the effects of real-time, anti-factor Xa (aFXa) level driven heparin dose adjustments. METHODS: This prospective clinical trial recruited adult microvascular surgery patients placed on a fixed-dose (500 units/h) unfractionated heparin infusion during their initial microsurgical procedure. Steady-state aFXa levels, a marker of unfractionated heparin efficacy and safety, were monitored. Patients with out-of-range aFXa levels received protocol-driven real-time dose adjustments. Outcomes of interest included aFXa levels in response to heparin 500 units/h, number of dose adjustments required to achieve goal aFXa levels, time to reach goal aFXa level, and 90-day clinically relevant bleeding and VTE. RESULTS: Twenty patients were recruited prospectively. None of 20 patients had any detectable level of anticoagulation in response to heparin infusions at 500 units/h. The median number of dose adjustments required to reach goal level was five, and median weight-based dose to reach goal level was 11.8 units/kg/h. Real-time dose adjustments significantly increased the proportion of patients with in-range levels (60 vs. 0%, p = 0.0001). The 90-day VTE rate was 5% and 90-day clinically relevant bleeding rate was 5%. CONCLUSIONS: Fixed-dose heparin infusions at a rate of 500 units/h do not provide a detectable level of anticoagulation after microsurgical procedures and are insufficient for the majority of patients who require VTE prophylaxis. Weight-based heparin infusions at 10 to 12 units/kg/h deserve future study in patients undergoing microsurgical procedures to increase the proportion of patients receiving adequate VTE prophylaxis.


Subject(s)
Anticoagulants/administration & dosage , Heparin/administration & dosage , Microsurgery , Preoperative Care , Venous Thromboembolism/prevention & control , Adult , Dose-Response Relationship, Drug , Female , Humans , Infusions, Intravenous , Male , Microsurgery/adverse effects , Middle Aged , Prospective Studies , Treatment Outcome , Venous Thromboembolism/drug therapy , Young Adult
10.
Plast Reconstr Surg Glob Open ; 6(2): e1673, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29616171

ABSTRACT

In this presentation of 2 consecutive cases of symptomatic juvenile breast hypertrophy in Ghana, we review the patient presentation, workup, and discuss outcomes following a combined technique of inferior pedicle stump with free nipple graft reduction mammoplasty. Surgical goals for treatment of gigantomastia were 2-fold: to resect adequate tissue to obtain symptomatic relief with improved quality of life, while avoiding a flat, boxy-appearing breast shape.

11.
Am J Surg ; 216(6): 1177-1181, 2018 12.
Article in English | MEDLINE | ID: mdl-29366487

ABSTRACT

BACKGROUND: Despite high expenditure, there is little national data on rates of complications following pressure ulcer repair. Complications, mortality and their predictors following surgical repair of pressure ulcers were evaluated. METHODS: Patients undergoing pressure ulcer repair were identified in the NSQIP database from 2005 to 2015. Regression models were used to identify risk factors for complications. RESULTS: 1248 cases were identified with a complication rate of 35.0%. Obesity was associated with increased risk of complications, whereas flap closure was associated with fewer complications. Thirty-day mortality was 3.3%. Elderly age and diabetes were associated with increased mortality. CONCLUSIONS: Elderly age, diabetes and dependency are associated with increased mortality following pressure ulcer surgery. Flap repair is associated with decreased complications. Pressure ulcer reconstruction requires careful patient selection and surgical technique to mitigate risks and mortality.


Subject(s)
Plastic Surgery Procedures/adverse effects , Postoperative Complications/epidemiology , Pressure Ulcer/complications , Pressure Ulcer/surgery , Surgical Flaps , Adult , Aged , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Pressure Ulcer/mortality , Retrospective Studies , Risk Factors , Survival Rate , Treatment Outcome
12.
Hand (N Y) ; 10(2): 184-90, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26034428

ABSTRACT

BACKGROUND: Arterialized venous flow-through (AVFT) flaps are useful in reconstructing small soft tissue defects. Currently, no guidelines exist for the use of AVFT flaps for reconstructing soft tissue defects in the digits of the hand. We retrospectively reviewed our experience with AVFT flaps and developed a selection process for vascular anastomoses. METHODS: We reviewed the use of AVFT flaps in a series of ten consecutive patients requiring reconstruction of small soft tissue defects of the fingers. RESULTS: Between 2006 and 2012, ten consecutive digital reconstructions were performed using AVFT flaps. Flap sizes ranged from 5 to 13.5 cm(2). Initial congestion was seen in all flaps and resolved within 3-7 days. Leeches were utilized in two cases. All cases achieved good functional results. Three illustrative cases from our series of ten are presented, each demonstrating key decision-making factors in selecting recipient and flap vessels for anastomosis. CONCLUSIONS: AVFT flaps appear congested post-operatively, resolving in days to weeks, and resulting in healthy coverage of digital soft tissue defects with good functionality. We suggest a selection process for the use of AVFT flaps in digital soft tissue reconstruction, based on dorsal vs. volar and proximal vs. distal defect location, and the flap's inherent venous architecture.

13.
Am J Surg ; 210(3): 512-6, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26054659

ABSTRACT

BACKGROUND: This study's purpose was to examine the national rate of breast cancer patients undergoing bilateral mastectomy (BM) and immediate breast reconstruction (IBR) and their associated complication rates. METHODS: Using the National Surgical Quality Improvement Program database, breast cancer patients undergoing mastectomy between 2005 and 2012 were identified. Rates in BM and IBR as well as associated complication rates were evaluated. Logistic regression was used to identify predictors of BM, IBR, and complications. RESULTS: A total of 56,905 breast cancer patients underwent mastectomy. The rate of BM tripled (9.14% vs 25.44%, P < .0001) and the rate of IBR increased by 50% (29.73% vs 44.68%, P < .0001). Complication rates were higher in patients undergoing BM compared with unilateral mastectomy (11.49% vs 9.52%, P < .0001) and in patients undergoing IBR compared with mastectomy alone (11.62% vs 8.91%, P < .0001). White race and age less than 40 years were predictors of patients undergoing BM and IBR. CONCLUSIONS: The rates of BM and associated IBR have increased significantly since 2005 despite higher complication rates. Further research is needed to understand the reasons for these trends.


Subject(s)
Breast Neoplasms/surgery , Mammaplasty/trends , Mastectomy/trends , Postoperative Complications/epidemiology , Age Factors , Comorbidity , Databases, Factual , Female , Humans , Logistic Models , Mammaplasty/statistics & numerical data , Mastectomy/statistics & numerical data , Middle Aged , Racial Groups , United States/epidemiology
14.
J Craniofac Surg ; 23(7 Suppl 1): 2011-3, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23154371

ABSTRACT

We present a rare case of transient oblong (segmental) anisocoria occurring at the time of limited orbital surgery. Observation of this previously undescribed phenomenon prompted us to review the relevant anatomy and physiology of the iris and the pharmacokinetics of lidocaine as it pertains to surgery in the region of the eyelids and the orbit.


Subject(s)
Anisocoria/etiology , Orbit/surgery , Orbital Fractures/surgery , Postoperative Complications , Adult , Anesthetics, Local/administration & dosage , Anesthetics, Local/pharmacokinetics , Bone Transplantation/methods , Device Removal , Dissection/methods , Electrocoagulation/methods , Female , Follow-Up Studies , Fracture Fixation, Internal/instrumentation , Fracture Fixation, Internal/methods , Humans , Iris/drug effects , Iris/innervation , Lidocaine/administration & dosage , Lidocaine/pharmacokinetics , Maxillary Sinus/surgery , Nasal Bone/injuries , Paranasal Sinus Diseases/surgery , Skull Fractures/surgery
15.
Mol Cell Biochem ; 363(1-2): 167-78, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22160856

ABSTRACT

The hypothesis of the present study is that cardiomyocytes subjected to prolonged ischemia, may release survival factors that will protect new cardiac cells from ischemic stress. We exposed neonatal rat cardiomyocyte primary cultures to hypoxia, collected the supernatant, treated intact cardiac cells by this posthypoxic supernatant, and exposed them to hypoxia. The results show cardioprotection of the treated cells compared with the untreated ones. We named the collected posthypoxic supernatant "conditioned medium" (CM), which acts in a dose-dependent manner to protect new cardiac cells from hypoxia: 100 or 75% of CM diluted in phosphate-buffered saline (PBS) protected cells as if they were not exposed to hypoxia (P < 0.001). When CM was removed from the cells before hypoxia, protection was not observed. CM also protected skeletal muscle cultures from hypoxia, but not cardiac cells against H(2)O(2)-induced cell damage. Finally, CM treatment protected the isolated heart in Langendorff set-up against ischemia. Smaller infarct size (9.9 ± 4.4% vs. 28.3 ± 8.5%, P < 0.05), better Rate Pressure Product (67 ± 11% vs. 48.6 ± 13.4%, P < 0.05) and better rate of contraction and relaxation were observed following ischemia and reperfusion (1341 ± 399 mmHg/s vs. 951 ± 349 mmHg/s, P < 0.05 and 1053 ± 347 mmHg/s vs. 736 ± 314 mmHg/s, P < 0.05). To conclude, there are factors that are released from the heart cells subjected to ischemia/hypoxia that protects cardiomyocytes from ischemic stress.


Subject(s)
Autocrine Communication , Myocardial Infarction/prevention & control , Myocardial Ischemia/prevention & control , Myocytes, Cardiac/metabolism , Animals , Animals, Newborn , Cell Hypoxia , Cells, Cultured , Culture Media, Conditioned/metabolism , Hydrogen Peroxide/toxicity , Male , Muscle Fibers, Skeletal/metabolism , Myocardial Contraction , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Ischemia/metabolism , Myocardial Ischemia/pathology , Myocardial Ischemia/physiopathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Perfusion , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Time Factors , Ventricular Function , Ventricular Pressure
16.
Biochem Pharmacol ; 81(10): 1219-27, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21376706

ABSTRACT

RATIONALE: Extracellular nucleotides have widespread effects and various cell responses. Whereas the effect of a purine nucleotide (ATP) and a pyrimidine nucleotide (UTP) on myocardial infarction has been examined, the role of different purine and pyrimidine nucleotides and nucleosides in cardioprotection against hypoxic stress has not been reported. OBJECTIVE: To investigate the role of purine and pyrimidine nucleotides and nucleosides in protective effects in cardiomyocytes subjected to hypoxia. METHODS AND RESULTS: Rat cultured cardiomyocytes were treated with various extracellular nucleotides and nucleosides, before or during hypoxic stress. The results revealed that GTP or CTP exhibit cardioprotective ability, as revealed by lactate dehydrogenase (LDH) release, by propidium iodide (PI) staining, by cell morphology, and by preserved mitochondrial activity. Pretreatment with various P2 antagonists (suramin, RB-2, or PPADS) did not abolish the cardioprotective effect of the nucleotides. Moreover, P2Y2 -/- , P2Y4 -/-, and P2Y2 -/-/P2Y4 -/- receptor knockouts mouse cardiomyocytes were significantly protected against hypoxic stress when treated with UTP. These results indicate that the protective effect is not mediated via those receptors. We found that a wide variety of triphosphate and diphosphate nucleotides (TTP, ITP, deoxyGTP, and GDP), provided significant cardioprotective effect. GMP, guanosine, and ribose phosphate provided no cardioprotective effect. Moreover, we observed that tri/di-phosphate alone assures cardioprotection. Treatment with extracellular nucleotides, or with tri/di-phosphate, administered under normoxic conditions or during hypoxic conditions, led to a decrease in reactive oxygen species production. CONCLUSIONS: Extracellular tri/di-phosphates are apparently the molecule responsible for cardioprotection against hypoxic damage, probably by preventing free radicals formation.


Subject(s)
Extracellular Fluid/metabolism , Myocytes, Cardiac/drug effects , Purine Nucleosides/pharmacology , Purine Nucleotides/pharmacology , Pyrimidine Nucleosides/pharmacology , Pyrimidine Nucleotides/pharmacology , Animals , Antioxidants/pharmacology , Cell Hypoxia , Cell Survival/drug effects , Cells, Cultured , Chelating Agents/pharmacology , Gene Knockout Techniques , Mice , Mice, Inbred C57BL , Mitochondria, Heart/physiology , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Purine Nucleosides/metabolism , Purine Nucleotides/metabolism , Purinergic Antagonists/pharmacology , Pyrimidine Nucleosides/metabolism , Pyrimidine Nucleotides/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Receptors, Purinergic P2/genetics , Receptors, Purinergic P2Y2/genetics , Stress, Physiological , Uridine Triphosphate/physiology
17.
Mol Cell Biochem ; 345(1-2): 153-60, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20730620

ABSTRACT

Activation of either the A(1) adenosine receptor (A(1)R) or the A(3) adenosine receptor (A(3)R), by their specific agonists CCPA and Cl-IB-MECA, respectively, protects cardiac cells in culture against ischemic injury. Yet the full protective mechanism remains unclear. In this study, we therefore examined the involvement of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK) phosphorylation in this protective intracellular signaling mechanism. Furthermore, we investigated whether p38 MAPK phosphorylation occurs upstream or downstream from the opening of mitochondrial ATP-sensitive potassium (K(ATP)) channels. The role of p38 MAPK activation in the intracellular signaling process was studied in cultured cardiomyocytes subjected to hypoxia, that were pretreated with CCPA or Cl-IB-MECA or diazoxide (a mitochondrial K(ATP) channel opener) with and without SB203580 (a specific inhibitor of phosphorylated p38 MAPK). Cardiomyocytes were also pretreated with anisomycin (p38 MAPK activator) with and without 5-hydroxy decanoic acid (5HD) (a mitochondrial K(ATP) channel blocker). SB203580 together with the CCPA, Cl-IB-MECA or diazoxide abrogated the protection against hypoxia as shown by the level of ATP, lactate dehydrogenase (LDH) release, and propidium iodide (PI) staining. Anisomycin protected the cardiomyocytes against ischemic injury and this protection was abrogated by SB203580 but not by 5HD. Conclusions Activation of A(1)R or A(3)R by CCPA or Cl-IB-MECA, respectively, protects cardiomyocytes from hypoxia via phosphorylation of p38 MAPK, which is located downstream from the mitochondrial K(ATP) channel opening. Elucidating the signaling pathway by which adenosine receptor agonists protect cardiomyocytes from hypoxic damage, will facilitate the development of anti ischemic drugs.


Subject(s)
Adenosine A1 Receptor Agonists/pharmacology , Adenosine A3 Receptor Agonists/pharmacology , Hypoxia/prevention & control , Myocytes, Cardiac/pathology , p38 Mitogen-Activated Protein Kinases/physiology , Adenosine/analogs & derivatives , Animals , Extracellular Signal-Regulated MAP Kinases/metabolism , Heart , Hypoxia/diet therapy , Myocytes, Cardiac/drug effects , Phosphorylation , Potassium Channels , Protective Agents/pharmacology , Rats
18.
Radiat Res ; 160(4): 452-9, 2003 Oct.
Article in English | MEDLINE | ID: mdl-12968929

ABSTRACT

In the present study, the effects of photodynamic therapy (PDT) with verteporfin on tumor blood flow and tumor regrowth were compared as verteporfin distributed in different compartments within the RIF-1 tumor. Tissue distribution of verteporfin was examined by fluorescence microscopy, and blood flow measurements were taken with a laser Doppler system. It was found that, at 15 min after drug administration, when verteporfin was mainly confined within the vasculature, PDT induced a complete arrest of blood flow by 6 h after treatment. PDT treatment at a longer drug-light interval (3 h), which allowed the drug to diffuse to the tumor interstitium, caused significantly less flow decrease, only to 50% of the initial flow in 6 h. A histological study and Hoechst 33342 staining of functional tumor vasculature confirmed the primary vascular damage and the decrease in tumor perfusion. The regrowth rate of tumors treated with 15-min interval PDT was 64% of that of the control group. However, when tumors were treated with 3-h interval PDT, the regrowth rate was not significantly different from that of the control, indicating that only the 15-min interval PDT caused serious damage to the tumor vascular bed. These results support the hypothesis that temporal pharmacokinetic changes in the distribution of the photosensitizer between the tumor parenchyma and blood vessels can significantly alter the tumor target of PDT.


Subject(s)
Fibrosarcoma/metabolism , Fibrosarcoma/physiopathology , Photochemotherapy/methods , Porphyrins/administration & dosage , Porphyrins/pharmacokinetics , Animals , Blood Flow Velocity/radiation effects , Female , Fibrosarcoma/drug therapy , Fibrosarcoma/pathology , Mice , Neoplasm Staging , Neoplasm Transplantation , Neoplasms, Radiation-Induced/drug therapy , Neoplasms, Radiation-Induced/metabolism , Neoplasms, Radiation-Induced/pathology , Photosensitizing Agents/administration & dosage , Photosensitizing Agents/pharmacokinetics , Tissue Distribution , Treatment Outcome , Verteporfin
19.
Cancer Res ; 63(5): 1025-33, 2003 Mar 01.
Article in English | MEDLINE | ID: mdl-12615718

ABSTRACT

Photodynamic therapy (PDT) with verteporfin (lipid form of benzoporphyrin derivative,benzoporphyrin derivative monoacid ring A) was used to treat radiation-induced fibrosarcoma tumors before X-ray treatment. When verteporfin was injected 3 h before light irradiation, the tumor partial pressure of oxygen (pO(2)) rose from a pretreatment value of 2.8 +/- 1 to 15.2 +/- 6.9 mm Hg immediately after light application was complete (P = 0.048). When the optical irradiation was given 15 min after verteporfin injection, the tumor pO(2) decreased slightly after treatment [i.e., 6.8 +/- 1.6 mm Hg (pretreatment) versus 4.1 +/- 0.3 mm Hg (posttreatment)], whereas control tumor pO(2) did not change significantly. In vitro study of the cellular oxygen consumption rate before and after PDT treatment indicated that the consumption rate decreased linearly with delivered optical dose and quantitatively matched the loss of cell viability as measured by a mitochondrial tetrazolium assay. Doppler measurements show that red cell flux is still patent immediately after treatment, indicating that oxygen should still be delivered to the tumor. Computational simulations of the oxygen supply from the vessels and the consumption from mitochondrial activity confirmed that if oxygen consumption is decreased in the presence of unhindered blood flow, the tumor oxygenation should rise, and the hypoxic fraction of the tumor should decrease. Combination treatments with PDT delivered (100 J/cm(2) optical dose, with 1 mg/kg benzoporphyrin derivative monoacid ring A injected 3 h before treatment) after radiation treatment (10 Gy from 300 keV source) were compared with PDT delivered simultaneously with radiation. Tumor regrowth assay showed that the delays to reach double the tumor volume for PDT alone and radiation alone were 2.7 +/- 1.6 and 3.2 +/- 1.7 days, respectively. When radiation was given before PDT, the delay was 5.4 +/- 1.4 days, and when PDT was given at the same time as radiation, the delay was 8.1 +/- 1.5 days. This observation indicates that the combined effect in the latter case was greater than additive (P = 0.049).


Subject(s)
Fibrosarcoma/drug therapy , Fibrosarcoma/radiotherapy , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , Porphyrins/pharmacology , Radiation Tolerance/drug effects , Animals , Basal Metabolism/drug effects , Cell Hypoxia/drug effects , Cell Survival/drug effects , Combined Modality Therapy , Computer Simulation , Female , Fibrosarcoma/blood supply , Fibrosarcoma/metabolism , Mice , Mice, Inbred C3H , Oxygen/metabolism , Oxygen Consumption/drug effects , Partial Pressure , Verteporfin
20.
Article in English | MEDLINE | ID: mdl-12062207

ABSTRACT

In this study, the vascular and tissue oxygen changes induced by photodynamic therapy in the RIF-1 tumor were examined, using electron paramagnetic resonance (EPR) oximetry. Two photosensitizers, including verteporfin (BPD-MA in a lipid-based formulation) and aminolevulinic acid-induced protoporphyrin IX (ALA-PPIX), were investigated with optical irradiation, sufficient to induce sub-curative damage in the tumor tissue, and the transient changes in PO(2) and vascular perfusion were examined. A large increase in tissue oxygenation (from 3 up to 9.5 mmHg) was observed when treated with ALA-PPIX based photodynamic therapy, which lasted during the treatment and a small residual increase that returned back to baseline levels by 48 h after treatment. With verteporfin-based photodynamic therapy, one group of animals was irradiated 15 min after injection and exhibited a small decrease in oxygenation relative to pre-irradiation levels. The second group was irradiated at 3 h after injection and exhibited a large increase in the average PO(2), (from 3 to 15 mmHg) by the end of the treatment. These observations indicate that photodynamic therapy significantly increases tissue PO(2) under certain treatment conditions, with the potential cause being either increased local blood flow or decreased local oxygen metabolic consumption due to cellular damage.


Subject(s)
Neoplasms/metabolism , Oxygen/analysis , Oxygen/metabolism , Photochemotherapy/methods , Photosensitizing Agents/classification , Photosensitizing Agents/pharmacology , Animals , Electron Spin Resonance Spectroscopy , Light , Mice , Neoplasm Transplantation , Partial Pressure , Photosensitizing Agents/analysis , Porphyrins/analysis , Porphyrins/pharmacology , Protoporphyrins/analysis , Protoporphyrins/pharmacology , Time Factors , Tumor Cells, Cultured , Verteporfin
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