Evolving therapeutic interventions for the management and treatment of Alzheimer's disease.

Alzheimer's Disease (AD) patients experience diverse symptoms, including memory loss, cognitive impairment, behavioral abnormalities, mood changes, and mental issues. The fundamental objective of this review is to discuss novel therapeutic approaches, with special emphasis on recently approved marketed formulations for the treatment of AD, especially Aducanumab, the first FDA approved moiety that surpasses the blood-brain barrier (BBB) and reduces amyloid plaques in the brain, thereby reducing associated cognitive decline. However, it is still in the phase IV trial and is to be completed by 2030. Other drugs such as lecanemab are also under clinical trial and has recently been approved by the FDA and is also discussed here. In this review, we also focus on active and passive immunotherapy for AD as well as several vaccines, such as amyloid-beta epitope-based vaccines, amyloid-beta DNA vaccines, and stem cell therapy for AD, which are in clinical trials. Furthermore, ongoing pre-clinical trials associated with AD and other novel strategies such as curcumin-loaded nanoparticles, Crispr/ cas9, precision medicine, as well as some emerging therapies like anti-sense therapy are also highlighted. Additionally, we discuss some off-labeled drugs like non-steroidal anti-inflammatory drugs (NSAID), anti-diabetic drugs, and lithium, which can manage symptoms of AD and different non-pharmacological approaches are also covered which can help to manage AD. In summary, we have tried to cover all the therapeutic interventions which are available for the treatment and management of AD under sections approved, clinical phase, pre-clinical phase or futuristic interventions, off-labelled drugs, and non-pharmacological interventions for AD, offering positive findings and well as challenges that remain.

A Spectrum of Solutions: Unveiling Non-Pharmacological Approaches to Manage Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a developmental disorder that causes difficulty while socializing and communicating and the performance of stereotyped behavior. ASD is thought to have a variety of causes when accompanied by genetic disorders and environmental variables together, resulting in abnormalities in the brain. A steep rise in ASD has been seen regardless of the numerous behavioral and pharmaceutical therapeutic techniques. Therefore, using complementary and alternative therapies to treat autism could be very significant. Thus, this review is completely focused on non-pharmacological therapeutic interventions which include different diets, supplements, antioxidants, hormones, vitamins and minerals to manage ASD. Additionally, we also focus on complementary and alternative medicine (CAM) therapies, herbal remedies, camel milk and cannabiodiol. Additionally, we concentrate on how palatable phytonutrients provide a fresh glimmer of hope in this situation. Moreover, in addition to phytochemicals/nutraceuticals, it also focuses on various microbiomes, i.e., gut, oral, and vaginal. Therefore, the current comprehensive review opens a new avenue for managing autistic patients through non-pharmacological intervention.

Therapy related AML in a case of chronic lymphocytic leukemia.

In comparison to the general population, patients with chronic lymphocytic leukemia (CLL) are at a higher risk of developing secondary malignancies. Several factors may contribute to pathogenesis, including direct effects of chemotherapy and radiation as well as the reduction of immune surveillance. Factors influencing the increased risk include the increasing age of CLL patients, chronic antigenic stimulation, and immune impairment related to CLL or chemotherapy. Compared to patients with acute myeloid leukemia (AML) that developed from de novo, therapy-related AML (t-AML) has had a poorer outcome. The range of cytogenetic abnormalities in therapy-related AML is comparable to that in de novo AML, although these patients have a significantly higher frequency of unfavourable cytogenetics, such as a complex karyotype or a deletion or loss of chromosomes 5 and/or 7. Herein, we describe a case of therapy-related AML with monocytic differentiation and t(8;16) with a residual CLL population. The aim of the present case is to highlight rare occurrence of therapy related AML with t(8;16) in CLL after fluderabine based chemotherapy (FCR: fludarabine, cyclophosphamide, and rituximab). This case also highlights flowcytometric immunophenotyping as an ideal tool to characterize secondary AML along with the identification of minimal residual disease of CLL clone, which could have ignored at t-AML diagnosis. The pathogenesis of myeloid and lymphoid malignancies as well as their co-existence can be studied by focusing on such patients. Factors predisposing to the development of t-AML should be studied further, which would help in monitoring these patients more carefully.

Cytomorphological evaluation of non-haematopoietic malignancies metastasizing to the bone marrow.

Bone marrow (BM) is one of the rare but important site of metastasis of solid tumors. The key steps of metastasis include invasion, intravasation, circulation, extravasation, and colonization. Tumor cells may express some adhesion molecules that promote the transmigration to the marrow space and link them to the marrow stroma with subsequent engraftment. It is important to detect the bone marrow metastasis for initial clinical staging, therapeutic selection, prognostic risk stratification, assessment of response to therapy and predicting relapse. Prognosis of non-hematopoietic malignancies with BM metastasis is dismal. Due to occulting and atypical clinical manifestations, bone marrow metastases can be easily missed or misdiagnosed, leading to higher mortality rates. The important factors on which the prognosis of patients with bone marrow metastases depends are primary tumor site, performance status, platelet count, and therapeutic regimens (systemic chemotherapy or palliative/supportive care). Further, in cases with BM metastasis with unknown primary sites, misdiagnosis can lead to delayed initiation of therapy and increased mortality. BM metastasis is seen in less than 10% of patients with metastatic cancer and is common in lung, breast or prostate carcinoma. Bone marrow metastasis can be presented as the initial presentation with hematological changes and may be misdiagnosed as a primary haematopoietic disorder. Leucoerythoblastic blood picture is the most common peripheral blood smear finding indicating BM metastasis, may be an indicator of associated BM fibrosis. Bone marrow aspiration and biopsy with immunohistochemistry (IHC) is an easy, cost effective and gold standard method of detection of BM metastasis. BM biopsy is superior to bone marrow aspirate for detection of metastasis. Morphology of metastatic cells is as per the primary site of tumor. Immunohistochemistry is a useful adjunct to morphology in reaching a definitive diagnosis even in case with carcinoma unknown primary (CUP) and also in diagnosing case of unsuspected malignancies. Though bone marrow is not among the most common site of involvement in CUP, which are liver, bone, lymph nodes and lung. But BM, if involved, the site of origin is determined using the immunohistochemistry panel applied to the metastatic deposits based on the morphology The aim of the review is to discuss the hematological findings of non-haematopoietic malignancies metastasizing to the bone marrow, emphasizing on histomorphology with IHC and its significance in establishing primary diagnosis in clinically unsuspected cases.

Pharmacological and analytical aspects of alkannin/shikonin and their derivatives: An update from 2008 to 2022.

Alkannin/shikonin (A/S) and their derivatives are naturally occurring naphthoquinones majorly found in Boraginaceae family plants. They are integral constituents of traditional Chinese medicine Zicao (roots of Lithospermum erythrorhizon). In last two decades significant increase in pharmacological investigations on alkannin/shikonin and their derivatives has been reported that resulted in discovery of their novel mechanisms in various diseases and disorders. This review throws light on recently conducted pharmacological investigations on alkannin/shikonin and their derivatives and their outputs. Various analytical aspects are also discussed and brief summary of patent applications on inventions containing alkannin/shikonin and its derivatives is also provided.

pH-Independent Dissolution and Enhanced Oral Bioavailability of Aripiprazole-Loaded Solid Self-microemulsifying Drug Delivery System.

The present study pursued the systematic development of a stable solid self-emulsifying drug delivery system (SMEDDS) of an atypical antipsychotic drug, aripiprazole (APZ), which exhibits poor aqueous solubility and undergoes extensive p-glycoprotein efflux and hepatic metabolism. Liquid SMEDDS excipients were selected on the basis of solubility studies, and the optimum ratio of surfactant/co-surfactant was determined using pseudo-ternary phase diagrams. The prepared formulations were subjected to in vitro characterization studies to facilitate the selection of optimum liquid SMEDD formulation containing 30% Labrafil® M 1944 CS, 46.7% Cremophor® EL and 23.3% PEG 400 which were further subjected to solidification using maltodextrin as a hydrophilic carrier. The optimized solid SMEDDS was extensively evaluated for stability under accelerated conditions, dissolution at various pH and pharmacokinetic profile. Solid-state attributes of the optimized solid SMEDDS indicated a marked reduction in crystallinity of APZ and uniform adsorption of liquid SMEDDS. Stability study of the solid SMEDDS demonstrated that the developed formulation retained its stability during the accelerated storage conditions. Both the optimized liquid and solid SMEDDS exhibited enhanced dissolution rate which was furthermore independent of the pH of the dissolution medium. Oral bioavailability studies in Sprague-Dawley rats confirmed quicker and greater extent of absorption with solid SMEDDS as evident from the significant reduction in Tmax in case of solid SMEDDS (0.83 ± 0.12 h) as compared with commercial tablet (3.33 ± 0.94 h). The results of the present investigation indicated the development of a stable solid SMEDDS formulation of APZ with enhanced dissolution and absorption attributes.

A crude method of DNA extraction and identification from exfoliated human buccal mucosa cells.

BACKGROUND: DNA analysis has a key role in forensic dentistry. However, techniques of DNA extraction and analysis are far from the reach of majority of medical professionals owing to its expensive set up. AIM: The present study was aimed at formulating a crude method of extracting DNA from human buccal mucosa cells using materials commonly available in the laboratory so that the medical professionals could get more exposure to molecular biology techniques. The objectives were to identify the DNA and to assess its purity. METHODS: Buccal mucosa cells from 10 healthy volunteers were taken for DNA extraction following the protocol of cell lysis, purification, and precipitation. DNA was identified using standardized techniques like Diphenylamine test and its purity was assessed using a spectrophotometer. A gel electrophoresis apparatus was also constructed using readily available materials. RESULTS: DNA was extracted from human buccal mucosa cells using a crude method. The standardized tests confirmed the presence of DNA contaminated with proteins. The locally made Gel electrophoresis model exhibited a faint halo around the wells instead of DNA bands. CONCLUSION: DNA extraction from human buccal mucosa cells was made possible using locally available materials and a crude method, but it was not of high purity.

Solid Pseudopapillary Neoplasm of the Pancreas in a Pediatric Patient with Associated Urogenital Anomalies.

We report a case of a 9-year-old girl presented to the outpatient department with abdominal pain and diagnosed as solid pseudopapillary neoplasm (SPN) with urogenital anomalies. SPN can occur in children with extrapancreatic abnormalities, especially urogenital abnormalities, so these anomalies should be looked for in children diagnosed with SPN and vice versa.

Hodgkin Lymphoma in a Case of Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors.

Chronic myeloid leukemia (CML) is characterized by increased and unregulated proliferation of granulocytic lineage in the bone marrow and presence of these immature myeloid cells in the peripheral blood with presence of Philadelphia (Ph) chromosome. Tyrosine kinase inhibitors are the most important drugs in the CML therapy and provide long disease-free survival. Due to the increased survival of CML patients with continual administration of these drugs, the chance of development of secondary malignancies may increase. The most common secondary malignancies are prostate, colorectal and lung cancer, non-Hodgkin lymphoma, malignant melanoma, non-melanoma skin tumors and breast cancer. Herein, we are describing a rare case of Hodgkin lymphoma in a patient of CML after ten year of primary disease presentation. Hodgkin lymphoma in a known case of CML is very rare and further studies are also needed to know the pathogenic relationship between the two entities and to assess the risk of secondary Hodgkin lymphoma in CML patients treated with tyrosine kinase inhibitors. CML itself is a risk factor for development of solid cancers and hematologic malignancies. In addition, patients on chemotherapy are immune-compromised and may be at greater risk of neoplasm driven by infectious agents such as Epstein-Barr virus.

Isolated Central Nervous System (CNS) Relapse in Paediatric Acute Promyelocytic Leukaemia: A Systematic Review.

INTRODUCTION: Extramedullary disease, as a whole, is rare in Acute Promyelocytic Leukaemia (APML). If at all relapse occurs, following sites are involved: Central Nervous System (CNS), skin, testes, mediastinum, gingiva, and ear. Isolated CNS relapses after complete morphological and molecular remission is rarer particularly in children. AIM: To review the literature systematically to find out the incidence of isolated CNS relapse in paediatric APML cases. MATERIALS AND METHODS: A systematic search of major databases (Medline, Pubmed and Google Scholar) was conducted. We included all types of studies that reported about incidence or prevalence of isolated CNS relapse in children upto 18 years of age with APML. RESULTS: A total of nine studies (with 10 cases of isolated CNS relapse) were included. Majority (70%) was high risk patients, and 60% were ≤six-year-old. Nearly, 50% were having the mean time to relapse <12 months and most (60%) of them were male. The children who died were having shorter time to CNS relapse (around 12 months), and were older (>6 to 18 years). CONCLUSION: In the present review, disease in the high-risk group, male sex, younger age (≤six-years-old), and Promyelocytic Leukaemia/Retinoic Acid Receptor Alpha (PML-RARA) detection was found to be associated with isolated CNS relapse in children with APML. Cerebrospinal fluid (CSF) examination along with immunophenotyping and Reverse Transcription polymerase Chain Reaction (RT-PCR) for PML-RARA is required for a definite diagnosis and early treatment of patients to improve overall survival.

Gastrointestinal Histoplasmosis: A Case Series.

Histoplasmosis is an invasive mycosis caused by inhalation of the spores of dimorphic fungi Histoplasma capsulatum. The disease manifests in the lung as acute or chronic pulmonary histoplasmosis and in severe cases gets disseminated in multiple organs like skin, adrenal gland, central nervous system, lymph node, liver, spleen, bone marrow, and gastrointestinal tract. It occurs most commonly in immunodeficient patients like HIV-positive patients and transplant recipients, while immunocompetent hosts are affected rarely. In cases of gastrointestinal histoplasmosis, the samples are collected for culture and biopsy should be sent for histopathological examination for definitive diagnosis. We conducted a retrospective study of colonic biopsies performed in the department of gastroenterology in a tertiary care hospital of north India from January 2014 to December 2015. Five cases of colonic histoplasmosis were diagnosed on histopathology out of which 4 patients were from north India while 1 patient was from Myanmar. The patients presented with various complaints, including loose stools, diarrhea, altered bowel habits, and gastrointestinal bleeding. The prognosis is very good after early and aggressive treatment while the disease is fatal if it remains untreated. In our study, 2 patients died within few days of diagnosis due to delay in the diagnosis, dissemination, and associated complications. Other patients were started on amphotericin B deoxycholate and are under follow-up. An early diagnosis of gastrointestinal histoplasmosis is important as appropriate treatment leads to long-term survival while untreated cases are almost fatal.

Significant Haematogone Proliferation Mimicking Relapse in Acute Lymphoblastic Leukaemia on Therapy.

Haematogones are benign B lymphoid precursors which may mimic neoplastic lymphoblasts and pose diagnostic difficulty especially when the percentage of haematogones exceeds 10% in the bone marrow. Flow cytometric analysis with combination of CD19/CD10/CD20/CD34/CD38/CD58 can be used to differentiate the two depending upon the difference in the fluorescence intensity between blasts and haematogones. We hereby present a case of Common Acute Lymphoblastic Leukaemia Associated Antigen (CALLA) positive Acute Lymphoblastic Leukaemia (ALL), in which patient presented with haematogone proliferation in bone marrow after 6 months of chemotherapy mimicking relapse. The distinction was made on flow cytometric immunophenotyping by using optimal antibody combination. Distinction of benign haematogones from neoplastic lymphoblasts is essential for disease management in cases of post chemotherapy or post marrow transplant, especially in patients of ALL. Flow cytometric immunophenotyping is reliable to distinguish haematogones from residual lymphoblasts in almost all cases when optimal antibody combinations are used.

Cytomorphometric analysis and morphological assessment of oral exfoliated cells in type 2 diabetes mellitus and healthy individuals: A comparative study.

CONTEXT: Oral exfoliative cytology is a simple, nonaggressive technique that is well accepted by patients. Therefore, it is an attractive option, which aids in the diagnosis and observation of epithelial atypias associated with oral mucosal diseases. AIMS: The aim of this study was to evaluate and compare the quantitative and qualitative alterations in exfoliative smears from type 2 diabetics and healthy individuals. PATIENTS AND METHODS: The study includes 30 type 2 diabetics and 30 healthy persons of both sexes. PAP and hematoxylin and eosin (H and E) stained smears were prepared from buccal mucosa (BM), tongue (T), floor of the mouth (FOM), and palate (P). Under a light microscope, 50 clearly defined unfolded epithelial cells were quantitatively evaluated for cellular area (CA), nuclear area (NA), and cellular-to-nuclear area ratio (CA:NA) and assessed for morphological features. STATISTICAL ANALYSIS: Collected data was manually entered into the Statistical Package for the Social Sciences version 13.5 for analysis. Student's t-test was used at 95% confidence interval. RESULTS: Quantitative assessment of the overall mean CA was less, mean NA was more, and mean CA:NA was less in diabetics than that in healthy persons at all the four sites. Diabetic oral cells showed qualiative cytoplasmic and nuclear alterations: cytoplasmic vacuoles, karyorrhexis, karyolysis, pyknosis, peri-nuclear halo, binucleation, nuclear vacuoles, inflammation, and microbial colonies. CONCLUSION: Oral cytology from type 2 diabetics is associated with detectable cytomorphological changes with alteration in size of the cell and nucleus, which is site specific, indicating epithelial cell degeneration in cytoplasm and nucleus.

Adrenal Histoplasmosis in Immunocompetent Patients Presenting as Adrenal Insufficiency.

OBJECTIVE: Histoplasmosis is an infectious disease caused by the dimorphic fungus Histoplasma capsulatum, endemic in central and eastern states of United States, South America and Africa. India is considered to be non-endemic area for histoplasmosis. Disseminated histoplasmosis may affect almost all systems. Disseminated histoplasmosis with asymptomatic adrenal involvement has been described in immunocompromised patients; whereas isolated adrenal involvement with adrenal insufficiency as the presenting manifestation of the disease is rare. MATERIAL AND METHOD: Twelve patients from a non-endemic area with adrenal histoplasmosis, who were immunocompetent and diagnosed as adrenal histoplasmosis by cytology/histopathology between January 2012 to December 2014 were studied. 18F-FDG PET/CT (fluorodeoxyglucose positron emission tomography/computed tomography) was used to assess the extent of involvement. RESULTS: There were a total of 12 immunocompetent males (mean age: 56.9 years). Ten patients had bilateral adrenal involvement and two had a unilateral left adrenal mass. All the patients had histopathologically/cytologically proven adrenal histoplasmosis. Two patients had simultaneous histoplasmosis of other sites, one in the epiglottis and the other in the alveolus. 18F-FDG PET/CT was performed in 10 patients showing high FDG uptake in the adrenals. All these patients received Amphotericin B and/or Itraconazole treatment that led to symptomatic improvement. CONCLUSION: A diagnosis of invasive fungal infection requires a high index of suspicion, especially in immunocompetent patients who present with nonspecific symptoms, clinical signs, laboratory and radiological features that can resemble adrenal neoplasms. Clinical specimens must be sent for cytopathology/histopathology together with fungal culture for a definite diagnosis and appropriate management.

Triple cancer: chronic lymphocytic leukemia with bladder and prostate carcinoma.

B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common lymphoproliferative disorder with an increased risk of developing subsequent neoplasms of epithelial and mesenchymal origin. The decreased immunity and B-cell dysfunction in CLL probably accounts for this emergence of second malignancies. We report a case of synchronous bladder transitional cell carcinoma (TCC) and prostatic carcinoma with CLL. A 74-year-old male who underwent transurethral resection of the prostate (TURP) for benign prostatic hyperplasia 2 years before, presented with recurrent urinary tract infection. Peripheral blood smear revealed leukocytosis with absolute lymphocytosis (absolute lymphocyte count: 37870 cells/mm³). Flow cytometric immunophenotyping revealed 75% abnormal lymphoid cells which were positive for CD 19, CD5, CD23, CD22, CD200, CD20 (moderate) with lambda light chain restriction and negative for CD3, CD10, FMC7, CD38, CD138, IgM, CD103, CD123. F Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) showed increased metabolic activity of the left lateral wall of the urinary bladder extending to the left UV junction, adjacent part of trigone and bladder neck region along with multiple heterogeneous enhancing areas with increased FDG avidity within the prostate. Transurethral resection of the bladder tumour by cystoscopy was performed. Histopathology showed high grade, muscle invasive urothelial carcinoma. Due to presence of uptake in the prostate, transurethral resection of the prostate was done and histopathology revealed adenocarcinoma of prostate (prostate specific antigen- positive), Gleason grade III+III and Gleason score 6. A high index of suspicion is required to detect synchronous and metachronous malignancies. Ancillary studies such as immunohistochemistry, flow cytometry and PET/CT are often essential for detection and an accurate diagnosis.