A Prospective Study of Patients Presenting With Pre-sternal Keloids.

INTRODUCTION: Keloid represents a pathological form of scarring. They are very common in the anterior chest area; nearly 50% of all keloids occur in this location. One of the reasons for this is that folliculitis and acne, known for triggering the development of keloids, are common on the anterior chest. The other reason is the tension load in this area due to the frequent movements of the upper limbs and the respiratory movements. These movements stretch the skin of the anterior chest horizontally. When this cyclical tension is imposed on the anterior chest wounds, there is an exacerbation and prolongation of the inflammation in the reticular dermis of the wound. These stresses induce the growth of keloids along the prevailing lines of skin tension. MATERIALS AND METHODS: We performed a prospective study in which patients were recruited over a period of one year. Patients presenting with symptomatic pre-sternal keloids and requesting treatment but were unwilling to undergo surgical intervention were included in this study. Patients with a history of previous thoracic surgery were excluded. Baseline assessment and documentation of the lesion were performed. The study patients received three sessions of intralesional injections of a combination of triamcinolone acetonide and hyaluronidase at four weekly intervals. The final assessment was performed four weeks after the third session. RESULTS: The study included 47 lesions in 47 patients with ages of the patients ranging from 16 to 70 years. Pre-sternal keloids were found to be more common among males than females, with a male-to-female ratio of 2.35:1. Patients presented with pre-sternal keloids that had been present for varying periods ranging from three to 81 months. All of our 47 patients completed the three sessions of the treatment. Following the treatment, there was an improvement in the patient's symptoms, as evidenced by the reduction in the mean pruritis scores and pain scores. There was an overall reduction in the size of the lesion. The decrease in the height of the lesions was more evident than the reduction in the craniocaudal or transverse dimensions of the lesions. There were improvements in Vancouver Scar Scale (VSS) vascularity scores and pliability scores following the treatment. CONCLUSION: We conclude that pre-sternal keloids should be considered as a distinct clinico-pathological entity. There are differences with regard to pathogenesis, clinical presentation, and management when compared to keloids elsewhere. Treatment with intralesional injections of a combination of triamcinolone acetonide and hyaluronidase effectively relieves the symptoms and may be considered in patients not willing to undergo surgical intervention. Recurrences can occur and need further treatments.

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.

Reconstruction of Foot and Ankle Defects: A Prospective Analysis of Functional and Aesthetic Outcomes.

INTRODUCTION: Reconstruction of foot and ankle defects requires selecting an appropriate durable and aesthetically appealing option. From the different options, the procedure's choice depends on the defect's size, location, and donor area's availability. Patients' main goal is to have an acceptable biomechanical outcome. MATERIALS AND METHODS: In this prospective study, we have included patients who had undergone reconstruction of the ankle and foot defects between January 2019 and June 2021. Patient demographics, location and size of the defect, different procedures, complications, sensory recovery, ankle hindfoot score, and satisfaction score were recorded. RESULTS: 50 patients with foot and ankle defects were enrolled in this study. All flaps survived except one free anterolateral thigh flap. Five locoregional flaps developed minor complications, and all skin grafts healed well. The Ankle Hindfoot Score outcome has no significant relation with the anatomical location of the defects and the reconstructive procedure. All patients reconstructed using random local flap and with free flap were satisfied with the aesthetic outcome. CONCLUSIONS: Because of limited soft tissue, local flap availability is restricted to small defects. Satisfaction rates are high in local and free flaps and are best suited for reconstructing the weight-bearing part of the foot. Bulky flaps should be avoided over the dorsum and ankle region.

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.

Bipedicle Frontal-Occipital Flap for Reconstruction of Post Avulsion Injury of Scalp Temporoparietal Region: A Case Report.

The reconstruction of the scalp following avulsion injury has always been a great challenge for plastic surgeons. Here we report a 25 yr old female presented with necrosis of left temporoparietal scalp skin over left temporo-parietal region following history of avulsion injury of the scalp four days back at all India Institute of Medical Sciences, Bhopal, India in 2018. After removal of the necrosed skin, the defect was successfully covered with Bipedicle fronto-occipital flap.

Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery.

Great progress has been made over the past decade in understanding the structural, functional, and pharmacological diversity of lipid GPCRs. From the first determination of the crystal structure of bovine rhodopsin in 2000, much progress has been made in the field of GPCR structural biology. The extraordinary progress in structural biology and pharmacology of GPCRs, coupled with rapid advances in computational approaches to study receptor dynamics and receptor-ligand interactions, has broadened our comprehension of the structural and functional facets of the receptor family members and has helped usher in a modern age of structure-based drug design and development. First, we provide a primer on lipid mediators and lipid GPCRs and their role in physiology and diseases as well as their value as drug targets. Second, we summarize the current advancements in the understanding of structural features of lipid GPCRs, such as the structural variation of their extracellular domains, diversity of their orthosteric and allosteric ligand binding sites, and molecular mechanisms of ligand binding. Third, we close by collating the emerging paradigms and opportunities in targeting lipid GPCRs, including a brief discussion on current strategies, challenges, and the future outlook.

Post-traumatic wounds over the dorsum of the foot - our experience.

Post-traumatic wounds over the dorsum of the foot are commonly seen in our practice. Road traffic accidents, crush injuries due to the fall of heavy objects and burns are common causes of these injures. The subcutaneous tissue in this region is very thin, and the tendons and bone are frequently exposed in these wounds. Since the skin is loosely attached to the underlying tendons, ligaments, and bones, the skin of the dorsum of the foot is also vulnerable to avulsion trauma. Added to this, there is a paucity of local tissues for coverage. Hence the management of these wounds is quite challenging. Through this article, we intend to describe our experience with traumatic dorsal foot wounds. A total of 33 patients were eligible according to the inclusion criteria and their details were included in the final analysis. There were 26 (78.79%) males and 7 (21.21%) females, with a male to female ratio of 3.71:1. The age of the study patients ranged from 8 to 62 years, with a mean age and standard deviation of 34.39 and 13.566 respectively. Majority of the study patients were in the 21-30 years age group (n=10, 30.3%). Road traffic accidents were the most common cause of traumatic dorsal foot wounds (n=20, 60.61%). Majority of the wounds showed features suggestive of infection (n=22, 66.67%) at presentation. Most of the patients in our study needed surgical intervention, in addition to medical management (n=28, 84.84%). Surgical procedures performed include split-thickness skin grafts, local flaps and free flaps. Early complications occurred in 5 (15.15%) patients and late complications in 2 (6.06%) patients. In conclusion, post-traumatic wounds of the dorsum of the foot are very common and pose a difficult reconstructive challenge. Skin grafts, local tissue flaps and free flap options are available for reconstruction; selection of the appropriate option should be individualized in a given patient. Local or distant flaps should be preferred in comparison to skin grafts, because of their long term durability and lesser chances of contractures. Reconstruction must consider form, function, and aesthetics.

Use of Dorsal Ulnar Artery Flap for Coverage of Arterio-Cutaneous Fistula over Post-Electrical Burn Scar: A Case Report.

We reported a 38 year old male patient who suffered from electric burn 2 years ago, and came with complaints of recurrent profuse bleeding from post electric burn scar over left wrist area since last 6-8 months. We successfully used the dorsal ulnar artery flap to cover the arterio-cutaneous fistula over the post-electrical burn scar.

Identification of FDA-approved drugs as novel allosteric inhibitors of human executioner caspases.

The regulation of apoptosis is a tightly coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed 5 compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that 4 out of the 5 drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC50 values ranging ~10-55 µM. Structural analysis of the docking poses show the 4 compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of 4 novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.

Imidazole Nitrogens of Two Histidine Residues Participating in N-H···N Hydrogen Bonds in Protein Structures: Structural Bioinformatics Approach Combined with Quantum Chemical Calculations.

Protein structures are stabilized by different types of hydrogen bonds. However, unlike the DNA double helical structure, the N-H···N type of hydrogen bonds is relatively rare in proteins. N-H···N hydrogen bonds formed by imidazole groups of two histidine residues have not been investigated. We have systematically analyzed 5333 high-resolution protein structures with resolution 1.8 Å or better and identified 285 histidine pairs in which the nitrogen atoms of the imidazole side chains can potentially participate in N-H···N hydrogen bonds. The histidine pairs were further divided into two groups, neutral-neutral and protonated-neutral, depending on the protonation state of the donor histidine. Quantum chemical calculations were performed on imidazole groups adopting the same geometry observed in the protein structures. Average interaction energies between the interacting imidazole groups are -6.45 and -22.5 kcal/mol for neutral-neutral and protonated-neutral, respectively. Hydrogen bond interaction between the imidazole moieties is further confirmed by natural bond orbital analyses of the model compounds. Histidine residues involved in N-H···N hydrogen bonds are relatively more buried and have low B-factor values in the protein structures. N-H···N hydrogen bond formed by a pair of buried histidine residues can significantly contribute to the structural stability of proteins.

Comparison of metal-binding strength between methionine and cysteine residues: Implications for the design of metal-binding motifs in proteins.

Metals play vital role in various physiological processes and are bound to biomolecules. Although cysteine sulfur is more frequently found as metal-binding ligand, methionine prefers to occur in copper-binding motifs of some proteins. To address methionine's lower preference in copper-binding sites in comparison to cysteine, we have considered copper-binding motifs (His-Cys-His-Met) from seven different high-resolution protein structures. We performed quantum chemical calculations to find out the strength of interactions between sulfur and metal ion in both Met and Cys residues. In the case of Cys, both neutral (CysH) and the deprotonated form (Cys-) were considered. We used two different levels of theory (B3LYP and M06-2X) and the model compounds methyl propyl sulfide, ethanethiol and ethanethiolate were used to represent Met, CysH and Cys- respectively. To compare the metal-binding strength, we mutated Met in silico to CysH/Cys- and performed the calculations. We also carried out calculations with wild-type Cys present in the same metal-binding motif. On average, interactions of Met with copper ion are stronger by 13-35kcal/mol compared to CysH. However, Cys- interactions with copper is stronger than that of Met by ~250kcal/mol. We then considered the entire metal-binding motif with four residues and calculated the interaction energies with the copper ion. We also considered Met→Cys- mutation in the motif and repeated the calculations. Interaction of the wild-type motif with the copper ion is ~160kcal/mol weaker than that of mutated motif. Our studies suggest the factors that could explain why Met is not as frequently observed as Cys in the metal-binding motifs. Results of these studies will help in designing metal-binding motifs in proteins with varying interaction strengths.

N-H···N Hydrogen Bonds Involving Histidine Imidazole Nitrogen Atoms: A New Structural Role for Histidine Residues in Proteins.

The amino acid histidine can play a significant role in the structure and function of proteins. Its various functions include enzyme catalysis, metal binding activity, and involvement in cation-π, π-π, salt-bridge, and other types of noncovalent interactions. Although histidine's imidazole nitrogens (Nδ and Nε) are known to participate in hydrogen bond (HB) interactions as an acceptor or a donor, a systematic study of N-H···N HBs with the Nδ/Nε atom as the acceptor has not been conducted. In this study, we have examined two data sets of ultra-high-resolution (data set I) and very high-resolution (data set II) protein structures and identified 28 and 4017 examples of HBs of the N-H···Nδ/Nε type from both data sets involving histidine imidazole nitrogen as the acceptor. In nearly 70% of them, the main-chain N-H bond is the HB donor, and a majority of the examples are from the N-H group separated by two residues (Ni+2-Hi+2) from histidine. Quantum chemical calculations using model compounds were performed with imidazole and N-methylacetamide, and they assumed conformations from 19 examples from data set I with N-H···Nδ/Nε HBs. Basis set superposition error-corrected interaction energies varied from -5.0 to -6.78 kcal/mol. We also found that the imidazole nitrogen of 9% of histidine residues forming N-H···Nδ/Nε interactions in data set II participate in bifurcated HBs. Natural bond orbital analyses of model compounds indicate that the strength of each HB is mutually influenced by the other. Histidine residues involved in Ni+2-Hi+2···Nδi/Nεi HBs are frequently observed in a specific N-terminal capping position giving rise to a novel helix-capping motif. Along with their predominant occurrence in loop segments, we propose a new structural role for histidines in protein structures.

Controlling in Vitro Insulin Amyloidosis with Stable Peptide Conjugates: A Combined Experimental and Computational Study.

Insulin aggregation, to afford amyloidogenic polypeptide fibrils, is an energetically driven, well-studied phenomenon, which presents interesting biological ramifications. These aggregates are also known to form around insulin injection sites and in diabetic patients suffering from Parkinson's disease. Such occurrences force considerable reduction in hormone activity and are often responsible for necrotic deposits in diabetic patients. Changes in physicochemical environment, such as pH, temperature, ionic strength, and mechanical agitation, affect insulin fibrillation, which also presents intrigue from the structural viewpoint. Several reports have tried to unravel underlying mechanisms concerning the aggregation process taking into account a three aromatic amino acid patch Phe(B24)-Phe(B25)-Tyr(B26) located in the C-terminal part of the B chain, identified as a key site for human insulin-receptor interaction. The present study describes design and inhibitory effects of novel peptide conjugates toward fibrillation of insulin as investigated by thioflavin T assay, circular dichroism, and AFM. Possible interaction of insulin with peptide-based fibrillation inhibitors reveals an important role of hydrophobic interactions in the inhibition process. Molecular dynamics simulation studies demonstrate that inhibitor D4 interacts with insulin residues from the helix and the C-terminal extended segment of chain B. These studies present a novel approach for the discovery of stable, peptide-based ligands as novel antiamyloidogenic agents for insulin aggregation.

Oxygen-aromatic contacts in intra-strand base pairs: analysis of high-resolution DNA crystal structures and quantum chemical calculations.

Three-dimensional structures of biomolecules are stabilized by a large number of non-covalent interactions and some of them such as van der Waals, electrostatic and hydrogen bond interactions are well characterized. Delocalized π-electron clouds of aromatic residues are known to be involved in cation-π, CH-π, OH-π and π-π interactions. In proteins, many examples have been found in which the backbone carbonyl oxygen of one residue makes close contact with the aromatic center of aromatic residues. Quantum chemical calculations suggest that such contacts may provide stability to the protein secondary structures. In this study, we have systematically analyzed the experimentally determined high-resolution DNA crystal structures and identified 91 examples in which the aromatic center of one base is in close contact (<3.5Ǻ) with the oxygen atom of preceding (Group-I) or succeeding base (Group-II). Examples from Group-I are overwhelmingly observed and cytosine or thymine is the preferred base contributing oxygen atom in Group-I base pairs. A similar analysis of high-resolution RNA structures surprisingly did not yield many examples of oxygen-aromatic contact of similar type between bases. Ab initio quantum chemical calculations on compounds based on DNA crystal structures and model compounds show that interactions between the bases in base pairs with oxygen-aromatic contacts are energetically favorable. Decomposition of interaction energies indicates that dispersion forces are the major cause for energetically stable interaction in these base pairs. We speculate that oxygen-aromatic contacts in intra-strand base pairs in a DNA structure may have biological significance.