Heel Pain Management in Haglund's Deformity Targeting Sural Nerve Branches under Ultrasound Guidance: Case Report.

Introduction: Haglund's deformity is an abnormality of the bone and soft tissue of the foot, also known as retrocalcaneal exostosis, Mulholland deformity, and "pump bump". The etiology is not well known. Probable causes include a tight Achilles tendon, a high arch of the foot, and hereditary. The clinical features consist of pain at the posterior aspect of the heel which is predominantly present when the patient begins to walk after a period of rest or inactivity. Case Report: We report a case of a 60-year-old teacher with left heel pain for 3 years, unable to stand or walk for more than 15 min due to pain. We diagnosed him as a case of Haglund's deformity and treated him with ultrasound-guided injections targeting the superficial branches of the sural nerve. This case report illustrates a rarely described modality for the management of heel pain due to Haglund's deformity. Targeting superficial branches of the Sural nerve under ultrasound guidance can act as a superior treatment modality for the management of heel pain due to Haglund's deformity. Conclusion: Haglund's deformity is a cause of pain in the hindfoot that should be taken into account in the differential diagnosis of any patient presenting with heel pain. Ultrasonography has proved to be an important cost-effective tool in the diagnosis and management of various ankle pathologies like Haglund's deformity, thereby reducing the sole dependence on surgical management. Targeting the superficial (cutaneous) branches of the sural nerve can give satisfactory long-term relief of heel pain in patients with Haglund deformity.

Hyperphagia and Down Syndrome.

CASE: A.Z. is a 14-year-old young boy with Down syndrome and intellectual disability. As a baby and toddler, A.Z. struggled with swallowing dysfunction and recurrent aspiration, which improved by the time he was school aged. At the age of 2 years, his body mass index (BMI) was 95.98% (Z score 1.75). During his early school-age years, A.Z. began eating a wider variety of foods. As he grew taller and remained active, his BMI improved briefly during this time. Between ages 10 and 12 years, concerns regarding increased appetite and excessive weight gain emerged. His BMI increased from 82.56% (Z score 0.94) to 98.27% (Z score 2.11) during this time. He became insatiable; he ate when he was happy, upset, or bored. He had a compulsive need to eat all day, which escalated while staying home during the COVID pandemic. Despite having complete meals and a variety of snacks, he overate and sought out food and snacks, no matter the time of the day. Food also became a source of contention and a trigger for verbally and physically aggressive behavior when parents attempted to restrict food intake. Behavioral therapy was recommended to address his eating patterns as a part of his behavioral management plan.Over time, many strategies were used, including a token economy reward system, setting firm limits around snacking and meals, creating a food schedule with times and forced choice options, use of coping skill training, a feelings thermometer, and communication supports. These interventions had moderate intermittent success; however, overeating and consequent power struggles continued to be the major challenge reported by the family.He was started on a long-acting stimulant medication daily, intended to address impulsive and aggressive behaviors, and with potential benefit of appetite reduction. However, although there were some improvements in behavior, there was little to no effect noted on his appetite. Of note, he was diagnosed with celiac disease and severe obstructive sleep apnea at this time. A.Z. remained compliant with his gluten-free diet despite the challenges he experienced with food seeking and portion control. Overall, despite making excellent progress in behavioral regulation and performing particularly well in structured settings outside the home (i.e., school or summer camp), A.Z. continued to binge eat and seek out food with his most recent BMI at 98.62% (Z score 2.20).CASE 2: C.J. is a 9-year-old boy with Down syndrome and intellectual disability. As a toddler, C.J. had a brief period of time in which he was noted to overeat or not sense when he was full and subsequently gag or vomit after meals. At age 5 to 6 years, C.J. began demonstrating a more voracious appetite and increased weight gain; his BMI was 99.43% (Z score 2.53). Behavioral strategies, such as food schedules with forced choice options, were recommended. C.J. responded with increased dysregulation to the limit setting. An additional trigger for C.J. was the irregular visitation schedule with his father. He also hid and hoarded food; for example, he often ate food and hid the wrappers in the trash. Locking the refrigerator and cabinets resulted in binging on whatever he could find, such as ketchup packets. If C.J. wanted food during a time outside of his schedule, he was provided a list of alternative activities to choose from. It was recommended that his parent portion foods for him and set clear expectations of eating in the kitchen alone.C.J. was trialed on a short-acting alpha-agonist agent for 1 year to help address some of his behavioral challenges. Despite initial improvement on this regimen, behavioral challenges reemerged, and his eating behaviors worsened, so the medication was stopped. After stopping the medication, C.J. responded well to the limit setting, including regulating his own portion sizes and using a portion control plate. The family believed that the short-acting alpha-agonist worsened his food-seeking behaviors, although this was not clinically apparent. Despite having continued affinity for certain foods and snacks, C.J. was no longer binge eating or hoarding and hiding food. His most recent BMI remained elevated at 99.24% (Z score 2.43).

Dihydrofolate reductase inhibitors: patent landscape and phases of clinical development (2001-2021).

INTRODUCTION: Dihydrofolate reductase (DHFR) plays an important role in the biosynthesis of amino acid and folic acid. It participates by reducing dihydrofolate to tetrahydrofolate, in the presence of nicotinamide dinucleotide phosphate cofactor, and has been verified by various clinical studies to use DHFR as a target for the treatment of cancer and various bacterial infections. AREA COVERED: In this review, we have disclosed patents of synthetics and natural DHFR inhibitors with diaminopyrimidine and quinazoline nucleus from 2001. Additionally, this review highlights the clinical progression of numerous DHFR inhibitors received from the last five years. EXPERT OPINION: From 2001 to 2021, numerous active chemical scaffolds have been introduced and are exposed as lead candidates that have entered clinical trials as potent DHFR inhibitors. Moreover, researchers have paid considerable attention to the development of a new class of DHFR inhibitors with higher selectivity and potency. This development includes synthesis of synthetic as well as natural compounds that are potent DHFR inhibitors. On the basis of literature review, we can anticipate that there are a huge number of novel active molecules available for the future that could possess superior abilities to target this enzyme with a profound pharmacological profile.

Clear cell variant of Oral Squamous cell carcinoma.

OBJECTIVE: Among the various histopathological variants of oral squamous cell carcinoma, clear cell variant is a rarity. (1) This report is a compilation of two cases which showed the presence of clear cells. The clear cells were of koilocytic type. Although clear cell variant of squamous cell carcinoma is more common in skin, few cases have been found in oral region also. (2) This variant is considered more aggressive than the others, and hence requires more aggressive treatment protocol. Being rare, the percentage of clear cells determines whether it should be considered as a clear cell variant. The literature has been evaluated for similar cases, and discussed about the clear cells and their origin. An effort has also been made to compile the reported cases of clear cell variant of OSCC.

Basal cell ameloblastoma: a rare entity expressed in a middle aged female.

OBJECTIVE: Ameloblastoma is a true neoplasm of enamel organ type tissue which does not undergo differentiation to the point of enamel formation. It is a benign, locally invasive tumour of the oral cavity, most commonly affecting the maxilla and the mandible. Histologically there are several variants of ameloblastoma, the basal cell type being the least reported one. In this paper, we are presenting a case of basal cell ameloblastoma of the mandible with a brief review of literature.

Oral submucous fibrosis: an etiological dilemma.

OBJECTIVE: Oral Submucous Fibrosis (OSF), is a well-recognized, oral potentially malignant disorder predominantly affecting the South- Asian countries. OSF causes unique generalized fibrosis of the submucosal oral soft tissues, resulting in marked rigidity of the oral mucosa leading to progressive inability to open the mouth, rigidity of lips and difficulty in protruding the tongue. In this review we have discussed the multifactorial etiology of this potentially malignant disorder, including Chillies, Nutritional Deficiencies, Inducible nitric oxide synthsis (iNOS), genetic and immunological predisposition; and most importantly the role of areca nut and the effect of copper content in it.

Peripheral odontogenic fibroma: a rare gingival neoplasm with clinico-pathological differential diagnosis.

The peripheral odontogenic fibroma (POdF) is a rare gingival neoplasm, characterised by relatively mature collagenous fibrous tissue and varying amounts of odontogenic epithelium. It can be described as a slow growing, firmly attached, solid and smooth gingival mass which may be present asymptomatically for years, which may cause displacement of adjacent teeth. The purpose of this article is to discuss a case of POdF, occurring in the maxillary anterior region, with detailed clinico-pathological differential diagnosis to clarify characteristic features of various gingival overgrowths to enhance easy identification.

Identification of the pattern of copper as an etiological factor in oral submucous fibrosis: a cytological study.

UNLABELLED: Oral Submucous Fibrosis (OSF) is a well-recognized, potentially malignant disorder causing generalized fibrosis of the submucosal oral soft tissues. Though this disease is believed to be multi-factorial, areca nut chewing has emerged as the most important causative factor for OSF. Areca nut is known to have high levels of copper, which is believed to cause lysyl oxidase associated fibrosis. AIM: To evaluate the pattern of copper in buccal mucosal cells of OSF patients, areca nut chewers and normal healthy individuals and to elicit the etiology of copper in OSF. MATERIALS AND METHODS: Patients were divided into three groups each comprising of 20 individuals- Healthy individuals (Group I); areca nut chewers without OSF (Group II); histopathologically confirmed OSF (Group Ill). The cytological smears made from each patient were stained with rhodanine stain for copper and evaluated for the qualitative and quantitative parameters of copper by using specific grading criteria. RESULTS: Quantitative estimation of copper content showed a marked variation in the mean values. Mean value of group I was 0.11 ± 0.39; group II was 1.09 ± 0.81 and group III was 2.34 ± 0.74 (p<0.001). Mean values for qualitative estimation of copper were - 0.01 ± 0.36 for group I, 1.08 ± 0.82 for group II and 2.39 ± 0.72 for group III (p<0.001). Chi square analysis was used to assess the percentage distribution of copper granules. This revealed that the colour intensity and the number of granules were seen to maximum in OSF patients, areca nut chewers without OSF having intermediated values and normal healthy individuals having the least values. CONCLUSION: An evident increase in the copper staining in group III individuals as compared to group I and group II was well appreciated. Increased copper levels in the local environment of the oral cavity indicates its role in lysyl oxidase associated submucosal fibrosis.

Inherent and acquired resistance to paclitaxel in hepatocellular carcinoma: molecular events involved.

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and is a major cause of cancer related deaths worldwide. Only 10 to 20% of HCC can be surgically excised. Therefore, chemotherapeutic intervention and treatment is essential for achieving favorable prognosis. However, therapeutic outcome of chemotherapy is generally poor owing to inherent resistance of cancer cells to the treatment or due to development of acquired resistance. To differentiate and delineate the molecular events, we developed drug resistant Hep3B cells (DRC) by treating cells with the increasing concentration of paclitaxel. We also developed a unique single cell clone of Hep3B cells (SCC) by selecting single cell colonies and screening them for resistant phenotype. Interestingly, both DRC and SCC were resistant to paclitaxel in comparison to parental Hep3B cells. We analyzed the contributory factors that may be involved in the development of resistance. As expected, level of P-glycoprotein (P-gp) was elevated in DRC. In addition, Caveolin-1 (Cav-1), Fatty acid synthase (FASN) and Cytochrome P450 (CYP450) protein levels were elevated in DRC whereas in SCC, FASN and CYP450 levels were elevated. Downregulation of these molecules by respective siRNAs and/or by specific pharmacological inhibitors resensitized cells to paclitaxel. Interestingly, these drug resistant cells were also less sensitive to vinblastine, doxorubicin and methotrexate with the exception of cisplatin. Our results suggested that differential levels of P-gp, Cav-1 and FASN play a major role in acquired resistant phenotype whereas FASN level was associated with the presentation of inherent resistant phenotype in HCC.

An intracellular domain fragment of the p75 neurotrophin receptor (p75(NTR)) enhances tropomyosin receptor kinase A (TrkA) receptor function.

Facilitation of nerve growth factor (NGF) signaling by the p75 neurotrophin receptor (p75(NTR)) is critical for neuronal survival and differentiation. However, the interaction between p75(NTR) and TrkA receptors required for this activity is not understood. Here, we report that a specific 29-amino acid peptide derived from the intracellular domain fragment of p75(NTR) interacts with and potentiates binding of NGF to TrkA-expressing cells, leading to increased neurite outgrowth in sympathetic neurons as a result of enhanced Erk1/2 and Akt signaling. An endogenous intracellular domain fragment of p75(NTR) (p75(ICD)) containing these 29 amino acids is produced by regulated proteolysis of the full-length receptor. We demonstrate that generation of this fragment is a requirement for p75(NTR) to facilitate TrkA signaling in neurons and propose that the juxtamembrane region of p75(ICD) acts to cause a conformational change within the extracellular domain of TrkA. This finding provides new insight into the mechanism by which p75(NTR) and TrkA interact to enhance neurotrophic signaling.

Field cancerization: concept and clinical implications in head and neck squamous cell carcinoma.

Cancer begins with multiple cumulative epigenetic and genetic alterations that sequentially transform a cell or a group of cells in a particular organ. The early genetic events might lead to clonal expansion of pre-neoplastic daughter cells in a particular tumor field. Subsequent genomic changes in some of these cells drive them towards the malignant phenotype. These transformed cells are diagnosed histopathologically as cancers owing to changes in cell morphology. Conceivably, a population of daughter cells with early genetic changes (without histopathology) remains in the organ, demonstrating the concept of field cancerization. The concept of "field cancerization" was first introduced by Slaughter et al in 1953 when studying the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. It was proposed to explain the development of multiple primary tumors and locally recurrent cancer. With present technological advancement and carefully designed studies using appropriate control tissue will enable identification of important molecular signatures in these genetically transformed but histologically normal cells. Such tumor-specific biomarkers should have excellent clinical utility. This review examines the concept of field cancerization in head and neck cancer and its possible utility in early detection, tumor progression and clinical significance.

Child with aplastic anemia: Anesthetic management.

Aplastic anemia is a rare heterogeneous disorder of hematopoietic stem cells causing pancytopenia and marrow hypoplasia with the depletion of all types of blood cells. This results in anemia, neutropenia and thrombocytopenia, which pose a challenge to both surgical and anesthetic management of such cases. We report a child with aplastic anemia who sustained traumatic ulcer on the arm and underwent split-thickness skin grafting under general anesthesia. There are only two case reports on anesthetic considerations in aplastic anemia patients in the literature. The anesthetic management is challenging because of the rarity of the disease, associated pancytopenia and immunosuppression.

Enhancement of carboplatin- and quercetin-induced cell death by roscovitine is Akt dependent and p53 independent in hepatoma cells.

PURPOSE: Hepatocellular carcinoma (HCC) is a common malignancy worldwide and has an annual occurrence of one million new cases. Novel therapeutic strategies of increased efficacy in the treatment of HCC-bearing patients would certainly be helpful. Hence, the authors explored the effect of combination treatment of roscovitine with chemotherapeutic drugs or quercetin (Qctn) in hepatoma cells, HepG2 and Hep3B. METHODS: Cell viability was assessed by MTT assay, cell growth assay, and nuclear morphological changes by DAPI staining. The altered expression of signaling proteins and apoptotic molecules was established by Western blotting. RESULTS: Roscovitine pretreatment considerably enhanced the drugs and Qctn-induced cell death in HepG2 and Hep3B cells. The exploratory studies revealed that augmented cell killing in HepG2 and Hep3B was mediated via Akt pathway and was independent of p53. pAkt was found to be significantly downregulated in combination treatment of roscovitine with carboplatin or Qctn. Corresponding to reduced expression of pAkt, the downstream molecules Bcl-2 and proactive forms of caspase 9 and caspase 3 were also downregulated indicating apoptosis. CONCLUSIONS: The present study reports for the first time, in hepatoma cells, the potentiation of carboplatin- and Qctn-induced cell death by the cell cycle inhibitor roscovitine. Roscovitine can thus be considered as a potential therapeutic target in combination with chemotherapeutic drugs or Qctn for treatment of HCC.

Neurocysticercosis: Acute presentation and intensive care management of two cases.

Neurocysticercosis (NCC), a common helminthic infestation in developing countries, may cause acquired epilepsy and neurological morbidities. Acute symptomatic seizure is the most common manifestation. The other clinical conditions include headache, hydrocephalus, chronic meningitis, focal neurological deficits, and psychological disorders. Altered sensorium and raised intracranial pressure (ICP) may require ventilatory support in an intensive care unit (ICU). Definitive diagnosis is made by identification of parasites in tissues or by a radiological demonstration of the scolex in cystic lesions. Antiepileptic drugs are used to control seizures after NCC. Steroids are generally administered along with antihelminthics, in order to control the edema and intracranial hypertension that may occur as a result of antiparasitic medications. In patients with intracranial hypertension, the priority is to manage the ICP before considering other treatment options. Antiparasitic drug treatment is never the mainstay of treatment, especially in the setting of elevated ICP. Here, we present the ICU management of two such cases.

Hyperthermia-associated carboplatin resistance: differential role of p53, HSF1 and Hsp70 in hepatoma cells.

Due to substantial technical improvements, clinical application of heat as a co-adjuvant in cancer treatment is acquiring new interest. The effect of hyperthermia on hepatoma cell lines Hep3B (p53 defective) and HepG2 (p53 wild type) when investigated led to an interesting observation that Hep3B cells are more susceptible to heat stress than HepG2 cells. In addition, heat-induced carboplatin resistance was observed in HepG2 cells only. To investigate the reasons, heat shock response was explored and it was observed that heat stress augmented heat shock protein 70 (Hsp70) expression levels in HepG2 and not in Hep3B cells. Furthermore, in HepG2 cells, induced Hsp70 is regulated by both p53 and heat shock transcription factor 1 (HSF1) wherein HSF1 levels are modulated by p53. The data implies that Hep3B are more susceptible to death upon heat stress than HepG2 cells because of non-induction of Hsp70. In addition, it was observed that inhibition of heat-induced p53/HSF1 diminishes Hsp70 levels, thereby restoring the sensitivity of heat-stressed HepG2 cells to carboplatin-triggered cell death. Collectively, the present study establishes interplay of p53, HSF1, and Hsp70 upon heat stress in HepG2 cells and also defines novel strategies to overcome constraints of utility of hyperthermia in cancer therapy through p53/HSF1-targeted therapeutic intervention.

Inhibition of Hsp27 and Hsp40 potentiates 5-fluorouracil and carboplatin mediated cell killing in hepatoma cells.

Heat shock proteins (Hsps) modulate several cellular functions and are ubiquitously present in cell. Here, we investigated alterations in the expression of Hsps and explored functional consequences of the same. Moreover, effect of quercetin (Qctn), an inhibitor of Hsps, on chemotherapeutic drugs treatment in hepatoma cells Hep3B and HepG2 was investigated. We for the first time report that 5-fluorouracil (5-FU) and carboplatin specifically induce expression of Hsp40 in addition to Hsp27 in Hep3B and HepG2 cells. Induction of Hsps following exposure to sub lethal dose of drugs is a cellular challenge to survival. However, under lethal environmental conditions with reduced cell viability, cells fail to sustain the induction of survival proteins, Hsp27 and Hsp40. Though Qctn itself, to certain extent is cytotoxic to cells, it potentiates the pro-apoptotic action of 5-FU and carboplatin, by inhibiting expression of Hsps. The increased cell killing correlates with decreased levels of procaspase-3. Furthermore, siRNA mediated knockdown of Hsp27 and Hsp40 diminishes survival of drugs exposed cells. Altogether, our data provides clear evidence that Hsp27 and 40 promote cell survival and inhibition of their expression does not allow cells to adapt to drug exposure and survive. Collectively, our novel findings on compelling action of 5-FU or carboplatin following knockdown of Hsp40 and that of Hsp27 highlights their strategic implications towards an effective therapy against HCC.

Mitomycin C induces bystander killing in homogeneous and heterogeneous hepatoma cellular models.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide that is particularly refractory to chemotherapy. Several studies have proposed combination chemotherapy regimen for HCC treatment. However, these therapies are not effective in regressing tumor and prolonging survival of patient's suffering from HCC. Therefore, the development of more effective therapeutic tools and new strategies for the treatment of HCC are urgently needed. Over the last decade much attention has been focused on "bystander effect" as a possible therapeutic strategy for the treatment of certain human tumors. Interest in this therapeutic approach originated from numerous reports describing the radiation induced bystander effect. However, the knowledge about chemotherapy induced bystander effect is still limited. Hence, chemotherapy induced bystander phenomenon in hepatoma cells was explored by utilizing Mitomycin C (MMC). RESULTS: MMC induced bystander killing was observed only in hepatoma cells and it did not occur in cervical cancer cells. MMC induced bystander killing was transferable via medium. It occurred in co-cultured cells indicating the involvement of secreted as well as membrane bound factors. FasL and TRAIL were detected in the conditioned medium from treated cells. In medium transfer experiment, pre-treatment with EDTA (a broad range protease inhibitor) diminished MMC induced bystander killing. Following drug exposure, expression of Fas and TRAIL receptors increased and treatment with neutralizing antibodies against FasL and TRAIL inhibited bystander killing. CONCLUSION: Our results highlight the therapeutic importance of MMC in the treatment of HCC and implicate role of membrane bound and secreted forms of FasL and TRAIL in MMC induced bystander killing.

Synthesis and antifungal activity of 1,2,3-triazole containing fluconazole analogues.

Fluconazole based novel mimics containing 1,2,3-triazole were designed and synthesized as antifungal agents. Their antifungal activities were evaluated in vitro by measuring the minimal inhibitory concentrations (MICs). Compounds 12, 15, and 16 were found to be more potent against Candida fungal pathogens than control drugs fluconazole and amphotericin B. The studies presented here provide structural modification of fluconazole to give 1,2,3-trazole containing molecules. Furthermore, these molecules were evaluated in vivo against Candida albicans intravenous challenge in Swiss mice and antiproliferative activities were tested against human hepatocellular carcinoma Hep3B and human epithelial carcinoma A431. It was found that compound 12 resulted in 97.4% reduction in fungal load in mice and did not show any profound proliferative effect at lower dose (0.001 mg/ml).