Evaluating Pedicled Pectoralis Major Myocutaneous Flap Reconstructions for Oral Malignancy and the Influence of Laterally Based Rotational Advancement Flap on Donor Site Integrity and Nipple Position in Male Patients.

Oral cancer poses a significant health burden, particularly in the male population of India. This study focuses on evaluating the outcomes of 48 pedicled Pectoralis major myocutaneous (PMMC) flap reconstructions in male patients with oral malignancy. Given the challenges associated with microvascular flap reconstructions, especially in advanced cancer cases, older patients, and resource-constrained settings, the PMMC flap still serves as a valuable alternative. The study introduces a novel approach by incorporating a laterally based rotational advancement flap (LBRA) to address donor site integrity and decrease the nipple-areolar complex (NAC) displacement. Traditionally, PMMC flap designs tend to cause inward shifting of the NAC during chest donor site closure, impacting the aesthetic outcome. Surgical techniques involved wide local resection, neck dissection, and PMMC flap reconstruction. The Flap design included a horizontal orientation with adjustments based on defect location. Additionally, a laterally based rotational flap from the chest aided in donor site closure. Results demonstrate the versatility and reliability of PMMC flap reconstructions, with no total flap necrosis or major complications observed in the 48 cases. The LBRA technique effectively mitigated NAC displacement. The study contributes to the existing literature by providing insights into the advantages of PMMC flap reconstructions and introducing a technique to optimize donor site closure and decrease the medial shifting of the nipple. The adaptability, reliable vascular supply, and simplified learning curve make the PMMC flap a preferred choice in resource-constrained settings with high patient demand. In conclusion, this research underscores the continued relevance and effectiveness of the PMMC flap in head and neck reconstruction, offering satisfactory cosmetic and functional results. The introduction of the LBRA technique adds a nuanced dimension to improve outcomes, particularly in male patients with oral malignancy.

Reconstruction of Scalp and Forehead Defects: Options and Strategies.

Background Aesthetic reconstruction of scalp and forehead defects with local flaps and minimal donor site morbidity is the primary goal of coverage. While selecting the coverage technique, essential factors such as size, location, and components of a defect, hair-bearing or non-hair-bearing nature of skin, status of the exposed skull, need for radiation, patient condition, availability of local tissue, and the potential for hairline distortion should be kept in mind. Materials and methods This is a retrospective analysis in which 54 patients who underwent soft tissue reconstruction of the scalp and forehead defects were included. The defect size was categorized into four groups: small: <4 cm2, medium: 4-50 cm2, large: 50-200 cm2, and very large: >200 cm2. Reconstruction of all defects was done according to the defect's size, location, and depth. All patients were regularly followed at intervals of two weeks, six weeks, and three months, respectively. The outcome was evaluated in terms of flap survival, flap coverage scale, the requirement of secondary treatment, postoperative complications, and final aesthetic appearance. Results In 54 consecutively treated patients with scalp and forehead defects, the male-to-female ratio was 2:1, and the overall mean age of participants was 34.8 years, ranging from 0.5 to 66 years. The most common etiology of the defect was trauma (16; 29.6%), and the most common location of the defect was combined (16; 29.6%). Rotation flap and primary closure were the most commonly performed procedure, each 12 (22.2%) in number. Out of 12 primary closure cases, two patients developed wound dehiscence because of infection. All cases of skin grafting healed well. All cases of transposition flap with skin grafting at the donor site went uneventful, and the dog ear at the base was revised later. One case of the bipedicle flap in which partial graft loss occurred at the donor area was managed with regrafting. Two cases of single rotation flap, one double rotation flap, and one free latissimus dorsi muscle flap developed distal necrosis. The excellent aesthetic outcome was found in all cases of primary closure and single and double rotation flaps. Conclusions Local flaps have an architecture similar to the recipient site, and low donor site morbidity results in an aesthetically more pleasant outcome. In our experience, scalp defects up to 50 cm2 were covered with the local scalp flaps with primary closure of the donor area. Defects ranging from 50 to 200 cm2 required local scalp flap with skin grafting at the donor area. Free tissue transfers are usually needed when the defect is very large, devoid of the periosteum, or with the calvarial defect.

Cubital fossa defect- our reconstructive experience with pedicle flaps.

Introduction: Cubital fossa wounds can be complicated by the non-availability of reliable, well-vascularized donor tissue. Closure with pliable and readily available donor tissue for cubital defect and early mobilization of the elbow joint is essential for better results. The authors did this study to see how best the results of cubital fossa defect cover can be achieved by pedicle flaps in a single stage without compromising the donor areas. Material and method: Patients having deep elbow wounds in which vital structures were lying exposed in the cubital region were included in this study. The patients were assessed for the availability of tissue for cover, reliability of flaps, flap pliability, the functional outcome of the elbow and donor site morbidity. Results: A total of 17 cases of cubital region defects are presented wherein closure of the wound by means of primary closure was not possible. Out of these, eight were covered with Pedicled Thoracodorsal Artery Perforator (TDAP) flaps, five with Pedicled split Latissimus Dorsi Muscle (SLDM) flaps and four with reversed lateral arm flaps (RLA). Post-operatively all the flaps were healthy, patients attained a good range of elbow joint movements with no clinically evident morbidity of the donor site. Conclusion: Cubital fossa defect coverage needs dedicated planning to obtain a sturdy tissue for cover. In the presence of local tissue damage or scarring, we have looked elsewhere to bring pliable and well-vascularized tissue which is reliable. The flaps we used have allowed single-stage reconstruction and early mobilization of the elbow joint with good functional recovery.

Bilateral Inferiorly Based Labia Majora Flaps: A Simple Technique for Post Episiotomy Dehiscence Coverage.

Episiotomy dehiscence because of infection is a cause of major physical, psychological and social problems. Management depends on the degree of injury. The loco-regional flap can be considered in recurrent dehiscence with loss of tissue. We report a case of a 26-year-old female who presented with a post episiotomy wound in the perineal region extending from the posterior fourchette to the anal opening. She gave the history of resuturing of dehiscence twice but the result was the same. On examination, there was a loss of skin and subcutaneous tissue between vaginal and anal opening with pouting of the anal and vaginal mucosa. Per rectal examination, the anal tone was normal. Her wound was covered with bilateral inferiorly based labia majora flaps with a good outcome. So, an inferiorly based labia majora flap can be a useful option in coverage of recurrent perineal dehiscence.

Reconstruction of Heel Soft Tissue Defects: An Algorithm Based on Our Experience.

BACKGROUND: Sensory recovery and durability of the flap is the primary goal of heel soft tissue reconstruction. From the different options, the choice of the flap depends on the size of the defect, its location, and the availability of the donor area. METHODS: In this retrospective study, 40 patients having heel defects were included from Jan 2016 to Dec 2018 in which different flaps were used for the reconstruction. The outcome was evaluated in terms of flap survival, recovery of sensation, the durability of coverage, and functional denouement. We also analysed the outcome between neuropathic and non-neuropathic ulcers of the heel. RESULTS: Out of 40 patients' medial plantar artery islanded flap was performed in eight cases, extended reverse sural flap in 16 cases, islanded reverse sural flap in six cases, local flaps in six cases, cross-leg flap in two cases, and free Latissimus Dorsi muscle flaps with Skin Graft cover in two cases. The patients were observed for a mean follow-up time of 15 months (12-20 months). Only two flaps showed marginal necrosis as an immediate complication. The majority of the flaps were tenacious in the follow-up period except for the six flaps that developed delayed ulceration. Return of protective sensation (P=0.006) and mean American Orthopaedic Foot and Ankle Society subjective score (P=0.025) was significantly higher in the non-neuropathic ulcer group. CONCLUSION: Locoregional flaps can cover most of the heel defects with a satisfactory outcome. The functional outcome was lower in the reconstructed neuropathic heel ulcer group.

Marjolin Ulcer: An Observational Epidemiological Study From a Tertiary Care Centre in India.

INTRODUCTION: Marjolin ulcer is a rare skin malignancy. Marjolin ulcer arises in zones of long-standing scars, inflammation, or chronic wounds. MATERIAL AND METHODS: The present study was conducted to assess the demographic profile and identify the predictors of recurrence in 55 patients with Marjolin ulcer admitted over 10 years. Patients underwent either wide local excision with 2-cm peripheral margin or amputation if clinically indicated due to joint involvement. Lymph nodes were dissected if found positive. Patients received adjuvant radiotherapy if tumor clearance was less than 4 mm or the draining lymph nodes were positive. RESULTS: Of the total 55 cases (mean age, 48.75 years; range, 24-74 years), 34 were men and 21 were women (male/female, 1.6:1). The most common cause of injury was flame burn (n = 32, 58%) followed by trauma (n = 10, 18%). The lower limb was frequently affected (n = 38, 69.1%). Twenty-six patients with resection margins less than 4 mm had received adjuvant radiotherapy. Among the 55 patients, 6 (11%) had undergone lymph node dissection. Local recurrence was noted within 18 months in 9 (16.35%) patients, of which 5 patients had a tumor-free margin of less than 4 mm. We found 2 predictors for local recurrence. First, moderately differentiated squamous cell carcinoma (P = 0.04) and, second, patients with lymph node involvement (P = 0.001). CONCLUSION: Marjolin ulcer is a high-risk skin tumor. Patients with positive lymph node or with moderately differentiated squamous cell carcinoma have high chances of recurrence. Frequent and intense follow-up is required for at least 2 years.

Effectiveness of Parkland formula in the estimation of resuscitation fluid volume in adult thermal burns.

PURPOSE: Acute burn resuscitation in initial 24 h remains a challenge to plastic surgeons. Though various formulae for fluid infusion are available but consensus is still lacking, resulting in under resuscitation or over resuscitation. Parkland formula is widely used but recently its adequacy is questioned in studies. This study was conducted to see how closely the actual volume of fluid given in our center matches with that of calculated volume by Parkland formula. METHODS: All patients admitted with more than 20% flame burn injury and within 8 h of incident were included in this study. Crystalloid solution for infusion was calculated as per Parkland formula; however, it was titrated according to the urine output. Data on fluid infusion were collected from patient's inpatient records and analyzed. RESULTS: The study included a total of 90 patients, about 86.7% (n = 78) of the patients received fluid less than the calculated Parkland formula. Rate of fluid administered over 24 h in our study was 3.149 mL/kg/h. Mean hourly urine output was found to be 0.993 mL/kg/h. The mean difference between fluid administered and fluid calculated by Parkland formula was 3431.825 mL which was significant (p < 0.001). CONCLUSION: The study showed a significant difference in the fluid infused based on urine output and the fluid calculated by Parkland formula. This probably is because fluid infused based on end point of resuscitation was more physiological than fluid calculated based on formulae.

Hepatitis C and alcohol exacerbate liver injury by suppression of FOXO3.

Hepatitis C virus (HCV) infection exacerbates alcoholic liver injury by mechanisms that include enhanced oxidative stress. The forkhead box transcription factor FOXO3 is an important component of the antioxidant stress response that can be altered by HCV. To test whether FOXO3 is protective for alcoholic liver injury, we fed alcohol to FOXO3(-/-) mice. After 3 weeks, one third of these mice developed severe hepatic steatosis, neutrophilic infiltration, and >10-fold alanine aminotransferase (ALT) elevations. In cell culture, either alcohol or HCV infection alone increased FOXO3 transcriptional activity and expression of target genes, but the combination of HCV and alcohol together caused loss of nuclear FOXO3 and decreased its transcriptional activity. This was accompanied by increased phosphorylation of FOXO3. Mice expressing HCV structural proteins on a background of reduced expression of superoxide dismutase 2 (SOD2; Sod2(+/-)) also had increased liver sensitivity to alcohol, with elevated ALT, steatosis, and lobular inflammation. Elevated ALT was associated with an alcohol-induced decrease in SOD2 and redistribution of FOXO3 to the cytosol. These results demonstrate that FOXO3 functions as a protective factor preventing alcoholic liver injury. The combination of HCV and alcohol, but not either condition alone, inactivates FOXO3, causing a decrease in expression of its target genes and an increase in liver injury. Modulation of the FOXO3 pathway is a potential therapeutic approach for HCV-alcohol-induced liver injury.

Up-regulation of Hedgehog pathway is associated with cellular permissiveness for hepatitis C virus replication.

UNLABELLED: Studies of the hepatitis C virus (HCV) life-cycle rely heavily on Huh7.5 cells, but the reasons why these cells are exceptionally permissive for HCV replication are not clear. Based on recent clinical observations, we hypothesized that the Hedgehog (Hh) pathway, which has not been previously associated with HCV replication, may be involved in the Huh7.5 phenotype of increased permissiveness. We tested this hypothesis by comparing levels of a variety of Hh-related cellular markers in Huh7.5 cells with the parental Huh7 cells, which are far less permissive. Here we demonstrate that Huh7.5 cells, when compared with Huh7 cells, have substantially decreased expression of epithelial markers, increased levels of mesenchymal markers, and markedly up-regulated Hh pathway activity: Shh, >100-fold, Gli1, >30-fold, Ptc, 2-fold. In Huh7.5 cells, we found that cyclopamine, an Hh pathway antagonist, reduced HCV RNA levels by 50% compared with vehicle and inactive isomer controls. Moreover, in Huh7 cells treatment with recombinant Shh ligand and SAG, both Hh pathway agonists, stimulated HCV replication by 2-fold and 4-fold, respectively. These effects were observed with both viral infections and a subgenomic replicon. Finally, we demonstrated that GDC-0449 decreased HCV RNA levels in a dose-response manner. CONCLUSION: We have identified a relationship between HCV and Hh signaling where up-regulated pathway activity during infection promotes an environment conducive to replication. Given that Hh activity is very low in most hepatocytes, these findings may serve to further shift the model of HCV liver infection from modest widespread replication in hepatocytes to one where a subset of cells support high-level replication. These findings also introduce Hh pathway inhibitors as potential anti-HCV therapeutics.

The homeodomain protein Cux1 interacts with Grg4 to repress p27 kip1 expression during kidney development.

The homeodomain protein Cux1 is highly expressed in the nephrogenic zone of the developing kidney where it functions to regulate cell proliferation. Here we show that Cux1 directly interacts with the co-repressor Grg4 (Groucho 4), a known effector of Notch signaling. Promoter reporter based luciferase assays revealed enhanced repression of p27(kip1) promoter activity by Cux1 in the presence of Grg4. Chromatin immunoprecipitation (ChIP) assays demonstrated the direct interaction of Cux1 with p27(kip1) in newborn kidney tissue in vivo. ChIP assays also identified interactions of Cux1, Grg4, HDAC1, and HDAC3 with p27(kip1) at two separate sites in the p27(kip1) promoter. DNAse1 footprinting experiments revealed that Cux1 binds to the p27(kip1) promoter on the sequence containing two Sp1 sites and a CCAAT box approximately 500 bp from the transcriptional start site, and to an AT rich sequence approximately 1.5 kb from the transcriptional start site. Taken together, these results identify Grg4 as an interacting partner for Cux1 and suggest a mechanism of p27(kip1) repression by Cux1 during kidney development.

Low intensity shear stress increases endothelial ELR+ CXC chemokine production via a focal adhesion kinase-p38{beta} MAPK-NF-{kappa}B pathway.

CXC chemokines with a glutamate-leucine-arginine (ELR) tripeptide motif (ELR(+) CXC chemokines) play an important role in leukocyte trafficking into the tissues. For reasons that are not well elucidated, circulating leukocytes are recruited into the tissues mainly in small vessels such as capillaries and venules. Because ELR(+) CXC chemokines are important mediators of endothelial-leukocyte interaction, we compared chemokine expression by microvascular and aortic endothelium to investigate whether differences in chemokine expression by various endothelial types could, at least partially, explain the microvascular localization of endothelial-leukocyte interaction. Both in vitro and in vivo models indicate that ELR(+) CXC chemokine expression is higher in microvascular endothelium than in aortic endothelial cells. These differences can be explained on the basis of the preferential activation of endothelial chemokine production by low intensity shear stress. Low shear activated endothelial ELR(+) CXC chemokine production via cell surface heparan sulfates, beta(3)-integrins, focal adhesion kinase, the mitogen-activated protein kinase p38beta, mitogen- and stress-associated protein kinase-1, and the transcription factor.

The Src tyrosine kinase pathway regulates thecal CYP17 expression and androstenedione secretion.

In order to evaluate the role of Src tyrosine kinase in thecal cell steroidogenesis, a pharmacological approach was utilized by treating enriched populations of mouse ovarian theca-interstitial cells in vitro with a direct Src kinase inhibitor, PP2. Inhibition of Src with PP2 increased both basal and forskolin-stimulated androstenedione secretion, and increased cytochrome P450 17-alpha hydroxylase-lyase (CYP17) promoter activity and steady state mRNA. PP2 did not change thecal levels of StAR mRNA. Inhibition of mitogen-activated protein kinase kinase, a downstream regulator of Src activity, using PD98059 also increased forskolin-stimulated secretion of androstenedione above forskolin alone, but had no effect on basal secretion of androstenedione. Src inhibition increased mitogen-activated protein kinase phosphatase-1 protein and decreased phosphorylation of SF-1, which correlated with increased CYP17 promoter activity and mRNA levels. These results implicate Src tyrosine kinase in the regulation of CYP17 and thecal androgen secretion.

Src tyrosine kinase regulates CYP17 expression and androstenedione secretion in theca-enriched mouse ovarian cells.

Src tyrosine kinase belongs to a non-receptor tyrosine kinase family and has been shown to be involved in G protein-coupled receptor desensitization and internalization. Stimulation of ovarian thecal cells with lutein-izing hormone (LH) activates adenylyl cyclase via a G protein-coupled LH receptor leading to an increase in cAMP. Subsequently, cAMP activates protein kinase A (PKA) that increases steroidogenesis. In order to evaluate the role of Src in thecal cell steroidogenesis, a pharmacological approach was utilized by treating a population of mouse ovarian theca-enriched cells (TEC) in vitro with two Src inhibitors, geldanamycin (GA) and herbimycin A (HA). Treatment of TEC with either GA or HA increased basal androstenedione secretion without alteration of cAMP. In the presence of forskolin, GA and HA treatment further increased androstenedione secretion. RT-PCR analysis of RNA from cells treated with GA for 8, 24, and 48 h revealed that GA increased cytochrome P450 17alpha-hydroxylase/lyase (CYP17) mRNA at 48 h. CYP17 promoter activity also increased after treatment of cells with GA and after co-transfection with a Src dominant negative plasmid. Inhibition of PKA using H89 blocked the effect GA and HA on androstenedione secretion. These results indicate that the pharmacological inhibitors of Src, GA and HA, tested in vitro increased thecal CYP17 promoter activity, CYP17 mRNA, and androstenedione secretion. In addition, GA and HA induced thecal androstenedione secretion may be cAMP independent but possibly requires PKA.

A possible role of HSP70 in mediating cardioprotection in patients undergoing CABG.

Heat shock protein 70 (HSP70) has been reported to be involved in myocardial self-preservation system. This study shows direct evidence of the effect of HSP70 on lymphocytes during ischemia and reperfusion in CABG (coronary artery bypass graft) surgery. Lymphocytes were separated from the blood obtained from 10 patients undergoing CABG at different time intervals. (i) Baseline samples (drawn before onset of bypass), (ii) ischemic samples (30 min after cross-clamp) and (iii) reperfusion samples (10 min after the cross clamp removal) were incubated with recombinant HSP70 and the cells were harvested after 36 h. The effect of HSP70 was monitored by measuring second messengers such as intracellular calcium, protein kinase C (PKC) and inositol triphosphate (IP3). In addition CD69 expression was also measured. The results showed a significant decrease in intracellular calcium and CD69 expression in ischemia and further in reperfusion samples as compared to their respective untriggered controls. PKC and IP3 levels however remained unaffected. The protective effect of HSP70 during ischemia and reperfusion could thus be attributed to decreasing intracellular calcium and CD69 expression. This study could therefore provide a mechanism of cardioprotection afforded by HSP70.

Release of pro-inflammatory mediators during myocardial ischemia/reperfusion in coronary artery bypass graft surgery.

Inflammation has been reported to play an important role in cardiac surgery under cardiopulmonary bypass due to systemic endotoxemia. In order to develop strategies against this injury in future we studied the combined effect of a number of inflammatory mediators in myocardial ischemia/reperfusion. Coronary sinus blood samples of ten patients undergoing coronary artery bypass graft surgery (CABG) were obtained at three time intervals (1) before onset of bypass (2) 30 min after cross clamp, and (3) 10 min after removal of cross clamp. The samples were subjected to evaluate levels of nitric oxide byproducts (nitrite and nitrate and citrulline), inflammatory cytokines (interleukin-2, interferon-gamma and interleukin-6), adhesion molecules, (CD62L and CD54), ratio of cell surface markers (CD4/CD8 and TCRalphabeta/gammadelta) cell activation markers (CD69 and HLA DR) and second messengers (protein kinase C, inositol 1,4,5 triphosphate and intracellular calcium levels). Ischemia and further reperfusion resulted in significant rise in nitrite and nitrate levels (p < 0.001), interleukin-6 (p < 0.01), CD62L (p < 0.001), CD69 (p < 0.05), protein kinase C (p < 0.001) and intracellular calcium (p < 0.001). A fall in CD4/CD8 ratio was observed on reperfusion. These changes during CABG show that ischemia/reperfusion leads to a release of an array of pro-inflammatory mediators of tissue injury, which could lead to pathophysiological changes. Hence the study suggests the need of some protective therapies against these inflammatory markers.

Solution structure of the MAPK phosphatase PAC-1 catalytic domain. Insights into substrate-induced enzymatic activation of MKP.

Inactivation of mitogen-activated protein kinases (MAPKs) by MAPK phosphatases (MKPs) is accomplished via substrate-induced activation of the latter enzymes; however, the structural basis for the underlying mechanism remains elusive. Here, we report the three-dimensional solution structure of the C-terminal phosphatase domain of the prototypical MKP PAC-1, determined when bound to phosphate. Structural and biochemical analyses reveal unique active site geometry of the enzyme important for binding to phosphorylated threonine and tyrosine of MAPK ERK2. Our study further demonstrates that the dynamic interaction between the N-terminal kinase binding domain and the C-terminal phosphatase domain of an MKP is directly coupled to MAPK-induced conformational change of the phosphatase active site, which is essential for eliciting its full enzymatic activity.