Using carbohydrate-based polymers to facilitate testicular regeneration.

Male infertility is a significant global issue affecting 60-80 million people, with 40%-50% of cases linked to male issues. Exposure to radiation, drugs, sickness, the environment, and oxidative stress may result in testicular degeneration. Carbohydrate-based polymers (CBPs) restore testis differentiation and downregulate apoptosis genes. CBP has biodegradability, low cost, and wide availability, but is at risk of contamination and variations. CBP shows promise in wound healing, but more research is required before implementation in healthcare. Herein, we discuss the recent advances in engineering applications of CBP employed as scaffolds, drug delivery systems, immunomodulation, and stem cell therapy for testicular regeneration. Moreover, we emphasize the promising challenges warranted for future perspectives.

Steering the course of CAR T cell therapy with lipid nanoparticles.

Lipid nanoparticles (LNPs) have proven themselves as transformative actors in chimeric antigen receptor (CAR) T cell therapy, surpassing traditional methods and addressing challenges like immunogenicity, reduced toxicity, and improved safety. Promising preclinical results signal a shift toward safer and more effective CAR T cell treatments. Ongoing research aims to validate these findings in clinical trials, marking a new era guided by LNPs utility in CAR therapy. Herein, we explore the preference for LNPs over traditional methods, highlighting the versatility of LNPs and their effective delivery of nucleic acids. Additionally, we address key challenges in clinical considerations, heralding a new era in CAR T cell therapy.

Breaking down barriers: The potential of smarter CAR-engineered NK cells against solid tumors.

Natural killer (NK) cells are considered to be the foremost fighters of our innate immune system against foreign invaders and thus tend to promptly latch onto the virus-infected and tumor/cancerous cells, killing them through phagocytosis. At present, the application of genetically engineered Chimeric antigen receptor (CAR) receptors ensures a guaranteed optimistic response with NK cells and would not allow the affected cells to dodge or escape unchecked. Hence the specificity and uniqueness of CAR-NK cells over CAR-T therapy make them a better immunotherapeutic choice to reduce the load of trafficking of numerous tumor cells near the healthy cell populations in a more intact way than offered by CAR-T immunotherapy. Our review mainly focuses on the preclinical, clinical, and recent advances in clinical research trials and further strategies to achieve an augmented and efficient cure against solid tumors.

Recent advances to Neuroprotection: repurposing drugs against neuroinflammatory disorders.

Cell death is a natural mechanism for biological clearance for the maintenance of homeostasis in a dynamic microenvironment of the central nervous system. Stress and various factors can lead to imbalance between cellular genesis and cell death leading to dysfunctionality and a number of neuropathological disorders. Drug repurposing can help bypass development time and cost. A complete understanding of drug actions and neuroinflammatory pathways can lead to effective control of neurodegenerative disorders. This review covers recent advances in various neuroinflammatory pathways understanding, biomarkers, and drug repurposing for neuroprotection.

Diagnostic and therapeutic value of EVs in lungs diseases and inflammation.

Extracellular vesicles (EVs) are membrane-derived messengers which have been playing an important role in the inflammation and pathogenesis of lung diseases. EVs contain varieties of DNA, RNA, and membrane receptors through which they work as a delivery system for bioactive molecules as well as intracellular communicators. EV signaling mediates tumor progression and metastasis. EVs are linked with many diseases and perform a diagnostic role in lung injury and inflammation so are used to diagnose the severity of diseases. EVs containing a variety of biomolecules communicate with the recipient cells during pathophysiological mechanisms thereby acquiring the attention of clinicians toward the diagnostic and therapeutic potential of EVs in different lung diseases. In this review, we summarize the role of EVs in inflammation with an emphasis on their potential as a novel candidate in the diagnostics and therapeutics of chronic obstructive pulmonary disease, asthma, and sarcoidosis.

Self-assembled and Zn(II)-coordinated dipeptide nanoparticles with membrane-rupturing action on bacteria.

Metal ion-coordinated self-assembled short-chain amino acid peptide molecules with multi-photon excitation wavelengths and their photoluminescence properties are advantageous for fluorescence-based diagnostics and treatments of biological diseases based on their extra features of antibacterial agents. We have designed a novel strategy based on tryptophan molecule coordinated with Zn(II) ions in the form of biocompatible spherical nanoparticles of diameter 30-80 nm which have been used for antibacterial treatments against different kinds of pathogenic bacteria (Escherichia coli, Salmonella typhimurium, and Pseudomonas). Preferably, we have used tryptophan-phenylalanine (Trp-Phe), a dipeptide molecule having tryptophan as principal material against E. coli strains as antimicrobial agents for surface rupturing and killing purposes. Furthermore, based on single amino acid, tryptophan, self-assembled and Zn(II)-coordinated dipeptide nanoparticles (Zn-DPNPs) were studied against three types of multi-drug-resistant bacteria as an active antimicrobial agent. These antibacterial efficient nanoparticles may have best alternative of antibiotic drugs for clinical applications. The capability of self-assembled fluorescence behavior of Zn-coordinated dipeptide molecules and higher hydrophobicity against bacterial cell wall will perform as antimicrobial fluorescent agents. KEY POINTS: • Zn(II) and Cu(II) better coordinated into self-assembled NPs. • Fluorescence signals showed interaction of NPs with gram -ve cell wall. • Significant surface-damaging effects were observed in the case of Cu-DPNPs and Zn-DPNPs.

Outcome of head injury in motorbike riders.

Objective: To determine the impact of helmet wearing on traumatic brain injury. Methods: We analyzed 400 cases of traumatic brain injury (TBI) in motorbike riders with and without helmet, from July 2017 to December 2020 presenting to the neurosurgery department at Jinnah Postgraduate Medical Center (JPMC), Karachi, Pakistan. The medical records were analyzed for CT scan findings, length of hospital stay, complications (mortality and disability), Glasgow Coma Scale (GCS) and Glasgow outcome score (GOS) at time of discharge. Result: A total of 400 patients with head injury due to motorbike accidents were included and all were male patients. They were equally divided into two groups, 200 in Group-A (with helmet) and 200 in Group-B (without helmet). Majority of the unhelmeted patients i.e. 102 (51%), needed admission in the Intensive Care Unit (ICU) compared to 70 (35%) in helmeted. When comparing non-helmeted patients to helmeted patients, the total median length of hospital stay was greater among non-helmeted patients (10 vs 05 days). Mortality was higher among non-helmeted patients seen in 50 (25%) as compared to 14 (7%) in helmeted patients. Overall, the good outcome was observed in 119 (59.5%) patients in Group-A as compared to70 (35%) patients in Group-B while 81 (40.5%) showed bad outcome in Group-A and 130 (64%) in Group-B. The failure to wear a helmet was found to be strongly linked with abnormal neuroimaging more complications, poor outcome and lower GCS on discharge as compared to patients using helmet. Conclusion: Lack of helmet use is linked to abnormal brain imaging, more complications, and a longer stay in the hospital after a head injury.

Risk factors, presentation and outcome of meningomyelocele repair.

OBJECTIVE: To determine the risk factors, presentation and outcome of meningomyelocele repair. METHODS: We reviewed 150 cases operated for meningomyelocele (MMC) at Jinnah Postgraduate Medical Centre Karachi between May 2015 and May 2018. Data of infants operated for MMC repair was extracted including socioeconomic status, maternal folate intake during pregnancy, head circumference, location and width of the defect, accompanying bladder and limb anomalies and treatments administered. Patients were followed up for a mean period of six months. RESULTS: A total of 150 children were evaluated, out of which there were 83(55.3%) males and 67(44.7%) females. All belonged to low socio economic group and prenatal maternal folate intake as risk factor was positive in 103(68.7%) cases. Mean head circumference was 37.4 cm (range, 30.7 to 50 cm). Based on their location, 83(55%) of the defects were lumbosacral, 38(25.4%) were lumbar, 16(10.7%) were thoraco lumbar, 10(6.7%) were thoracic and three (2%) were cervical. Mean size of the meningomyelocele sac was 4.3 cm×5.6 cm (range, 1cm×2 cm to 11cm×8.4cm) and 21(14%) of the babies had a skin defect requiring flap. According to accompanying anomalies, 98(65.3%) of the babies had hydrocephalus, 13(9%) had club foot, four (2.7%) had diastematomyelia and three (2%) had tethered cord. Eighty seven (58%) patients had neurological deficit pre operatively and eight (5.4%) patients with normal power deteriorated after surgery out of which five (3.3%) developed paraplegia and three (2%) developed paraparesis. CSF leak was the major complication encountered in 16(11%) followed by meningitis in seven (5%), while the overall mortality was four (2.6%). CONCLUSION: The practice of periconceptional folic acid supplementation is essential to reduce the prevalence of neural tube defects (NTDs) in the developing world. Improved maternal nutrition with access to quality antenatal care is vital to decrease the prevalence and health burden.

Freehand pedicle screw fixation: A safe recipe for dorsal, lumbar and sacral spine.

OBJECTIVE: To determine outcome of freehand pedicle screw fixation for dorsal, lumbar and sacral fractures at a tertiary care centre in the developing world. METHODS: A retrospective review was performed of 150 consecutive patients who underwent pedicle screw fixation from January 1, 2012 to 31st December 2017. A total of 751 pedicle screws were placed. Incidence and extent of cortical breach by misplaced pedicle screw was determined by review of intra-operative and post-operative radiographs and/or computed tomography. RESULTS: Among the total 751 free hand placed pedicle screws, four screws (0.53%) were repositioned due to a misdirected trajectory towards the disc space. six screws (0.79%) were identified to have cause moderate breach while four screws (0.53%) cause severe breach. There was no occurrence of iatrogenic nerve root damage or violation of the spinal canal. CONCLUSION: Free hand pedicle screw placement based on external landmarks showed remarkable safety and accuracy in our center. The authors conclude that assiduous adherence to technique and preoperative planning is vital to success.

Impact of depressed skull fracture surgery on outcome of head injury patients.

OBJECTIVE: To assess outcomes in surgically managed patients with depressed skull fractures and associated moderate to severe head injury. METHODS: The study was conducted in the Department of Neurosurgery Jinnah Postgraduate Medical Centre, Karachi, from January 2016 to December 2017. We analyzed 90 patients with depressed skull fracture managed surgically from January 2015 to December 2016. The patients selected for this study belonged to all age groups with clinically palpable depressed skull fracture confirmed by CT brain with bone window. Outcome was assessed by Glasgow outcome score. RESULTS: Total 90 patients were included in the study. Sixty (66.7%) were male and 30 (33.3%) were female with mean age of years 27.58+11.329. Among 90 patients, 38.8% were aged between 21 and 30 years. Road traffic accident was seen in 72 (80%) patients. The commonest site of fracture was frontal region in 50 patients (55.6%). GCS improved post operatively on comparison to preoperative. Five patients expired. CONCLUSION: Depressed skull fracture is common neuro surgical issue. Timely surgical management gives excellent results by decreasing morbidity and mortality.

Outcome of burr-hole aspiration of brain abscess.

OBJECTIVE: To determine the clinical outcome of burr-hole aspiration of brain abscess. METHODS: We analyzed 100 cases of intracranial abscess, treated surgically from January 2015 and October 2016 at Jinnah Postgraduate Medical Centre (JPMC). All patients were treated with burr hole aspiration. Medical records were analyzed for demographics, clinical presentation, predisposing factors, abscess location on imaging and clinical outcomes were charted. RESULTS: The study included 100 patients with 73 (73%) males and 27 (27%) females with a mean age of 36.69±10.96 years. Mean duration of signs and symptoms was 8.50±4.2 days. The most common presenting complaint was altered sensorium in 70 (70%) patients and commonest source of infection was otitis media seen in 27 patients (27%). The GCS on presentation was 13 in 57 (57%) cases. The parietal region was the most common site in 43 patients (43%), followed by frontal region in 33 patients (33%). Complete resolution of abscess with recovery of preoperative neuro-deficit was seen in 77 (77%) patients and recovery with major neuro-deficit was observed in 10 (10%) cases while 13 (13%) patients expired. CONCLUSION: Early diagnosis, optimum follow-up and timely burr-hole aspiration are the keys in the proper management of brain abscess.

Posterior occipito cervical decompression with fixation and fusion in Cranio vertebral junction compression.

OBJECTIVE: To find out the clinical outcome of posterior decompression with occipitocervical fixation and fusion in patients with Craniovertebral junction instability. METHODS: Eighty consecutive patients of cranio vertebral junction (CVJ) compression were treated in the department of neurosurgery, Jinnah Postgraduate Medical Centre (JPMC), Karachi over a period of 05 years from 1st January 2012 till 31st August 2016. All patients underwent posterior decompression with occipitocervical fusion (OCF) and fixation. The clinical outcome was assessed by Japanese Orthopedic Association (JOA) score and grading. RESULTS: Out of 80 patients with CVJ instability, 64 (80%) were due to non traumatic causes, while 16 (20%) were secondary to trauma. All 80 patients(100%) showed post operative relief in pain. Sixty four (80%) patients showed improvement in power post operatively while six (7.5%) had no change, four (5%) showed deterioration and six (7.5%) patients expired. Sixty four (80%) patients had improvement of the JOA scores at last follow-up. According to etiology, the JOA score for patients with trauma improved in 12(75%) patients and 52(81.25%) for non traumatic causes while six patients (7.5%) expired. Fusion was achieved in 64 (80%) patients at last follow-up. CONCLUSION: Posterior decompression with occipitocervical fusion and fixation is safe and can be recommended in cases of CVJ compression.

Lateral mass screw fixation in cervical spine injury.

OBJECTIVE: To determine clinical outcome in patients with cervical injury after lateral mass screws fixation in a tertiary care hospital. METHODS: This study included 88 patients, with cervical injury confirmed radiologically. Patients <12 or >70 years, with traumatic discs, cord compression without subluxation and previously operated on cervical spine were excluded from this study. All patients underwent fixation with lateral mass screws through posterior approach under fluoroscopic guidance. Frankel grading was used to assess the clinical status of these patients pre-operatively & post-operatively. RESULTS: There were 60(68.18%) males and 28(31.8%) females. The ages varied from 18 to 55 years with a mean of 32 yrs ± 8 yrs. The most common level of injury was C5-C6 in 46(52%) patients. According to Frankel grading system, 35 (39.8%) patients were placed in Grade A, 15(17.05%) in Grade B, 22(25%) in Grade C, 12 (13.6%) in Grade D, four (4.5%) in Grade E on admission. Postoperatively, 16 (18.2%) patients were placed in Grade A, 23 (26.1%) in Grade B, eight (9.1%) in Grade C, nine (10.2%) in Grade D and 26(29.6%) patients in Grade E with an overall improvement in neurological function in 51(58%) and power in 37(42%) patients. The major complications encountered were respiratory infections in 10(11.36%) and wound infection in four (4.5%) while eight (9.1%) patients expired. CONCLUSION: Lateral mass screws technique is a safe and effective method for cervical fixation after proper reduction.

Decreased Langerhans cell responses to IL-36γ: altered innate immunity in patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease caused by human papillomaviruses (HPVs) types 6 and 11 that is characterized by the polarization of adaptive immune responses that support persistent HPV infection. Respiratory papillomas express elevated mRNA levels of IL-36γ, a proinflammatory cytokine in comparison to autologous clinically normal laryngeal tissues; however there is no evidence of inflammation in these lesions. Consistent with this, respiratory papillomas do not contain TH1-like CD4(+) T-cells or cytotoxic CD8(+) T-cells, but instead contain a predominance of TH2-like and T regulatory cells (Tregs). In addition, papillomas also are infiltrated with immature Langerhans cells (iLCs). In this study, we show that papilloma cells express IL-36γ protein, and that human keratinocytes transduced with HPV11 have reduced IL-36γ secretion. We now provide the first evidence that peripheral blood-derived iLCs respond to IL-36γ by expressing inflammatory cytokines and chemokines. When stimulated with IL-36γ, iLCs from patients with RRP had lower expression levels of the TH2-like chemokine CCL-20 as compared with controls. Patients' iLCs also had decreased steady state levels of CCL-1, which is a proinflammatory chemokine. Moreover, CCL-1 levels in iLCs inversely correlated with the severity of RRP. The combined decrease of TH1- and a TH2-like chemokines by iLCs from patients could have consequences in the priming of IFN-γ expression by CD8(+) T-cells. Taken together, our results suggest that, in RRP, there is a defect in the proinflammatory innate immune responses made by iLCs in response to IL-36γ. The consequence of this defect may lead to persistent HPV infection by failing to support an effective HPV-specific, TH1-like and/or Tc1-like adaptive response, thus resulting in the predominant TH2-like and/or Treg micromilieu present in papillomas.

Emerging insights into the impacts of heavy metals exposure on health, reproductive and productive performance of livestock.

Heavy metals, common environmental pollutants with widespread distribution hazards and several health problems linked to them are distinguished from other toxic compounds by their bioaccumulation in living organisms. They pollute the food chain and threaten the health of animals. Biologically, heavy metals exhibit both beneficial and harmful effects. Certain essential heavy metals such as Co, Mn, Se, Zn, and Mg play crucial roles in vital physiological processes in trace amounts, while others like As, Pb, Hg, Cd, and Cu are widely recognized for their toxic properties. Regardless of their physiological functions, an excess intake of all heavy metals beyond the tolerance limit can lead to toxicity. Animals face exposure to heavy metals through contaminated feed and water, primarily as a result of anthropogenic environmental pollution. After ingestion heavy metals persist in the body for an extended duration and the nature of exposure dictates whether they induce acute or chronic, clinical or subclinical, or subtle toxicities. The toxic effects of metals lead to disruption of cellular homeostasis through the generation of free radicals that develop oxidative stress. In cases of acute heavy metal poisoning, characteristic clinical symptoms may arise, potentially culminating in the death of animals with corresponding necropsy findings. Chronic toxicities manifest as a decline in overall body condition scoring and a decrease in the production potential of animals. Elevated heavy metal levels in consumable animal products raise public health concerns. Timely diagnosis, targeted antidotes, and management strategies can significantly mitigate heavy metal impact on livestock health, productivity, and reproductive performance.

Extracellular Vesicles: the Next Frontier in Pregnancy Research.

Extracellular vehicles (EVs) have been involved in several aspects of pregnancy, including endometrial receptivity, embryo implantation, and embryo-maternal communication showing them associated with pregnancy disorders, such as preeclampsia, gestational diabetes mellitus, and preterm birth. Further research is warranted to fully comprehend the exact pathophysiological roles of EVs and to develop new therapies targeting EVs thereby improving pregnancy outcomes. Herein, we review the recent knowledge on the multifaceted roles of EVs during pregnancy and address the majority of the molecular interactions between EVs, maternal, and fetal cells with an emphasis on disorders of pregnancy under the influence of EVs. Moreover, we also discuss its applications in clinical trials followed by prospects.

Multifaceted role of TRIM21 in inflammation.

Tripartite motif (TRIM) family members participate in a variety of cellular activities, such as intracellular signaling, development, cellular death, protein quality control, immunological defense, waste degradation, and the emergence of cancer. These proteins usually act as E3 ubiquitin ligase. The final line of resistance against infectious viruses is a cytosolic ubiquitin ligase and antibody receptor called TRIM containing 21. TRIM21, a protein with a tripartite structure, has been linked to autoimmune erythematosus, Sjogren's disorder, and innate immunity. TRIM21 may either promote the formation of specific cancer-activating proteins, resulting in their proteasomal degradation, or it may do neither, depending on the kind of cancer and cancer-causing trigger. The current research has shown that the antiviral action of TRIM mostly depends on their role as E3-ubiquitin ligases and a significant portion of the TRIM family mediates the transmission of innate immune cell signals and the subsequent production of cytokines. We highlighted the function of TRIM family members in various inflammatory diseases.

Functional role of autophagy in testicular and ovarian steroidogenesis.

Autophagy is an evolutionarily conserved cellular recycling process that maintains cellular homeostasis. Despite extensive research in endocrine contexts, the role of autophagy in ovarian and testicular steroidogenesis remains elusive. The significant role of autophagy in testosterone production suggests potential treatments for conditions like oligospermia and azoospermia. Further, influence of autophagy in folliculogenesis, ovulation, and luteal development emphasizes its importance for improved fertility and reproductive health. Thus, investigating autophagy in gonadal cells is clinically significant. Understanding these processes could transform treatments for endocrine disorders, enhancing reproductive health and longevity. Herein, we provide the functional role of autophagy in testicular and ovarian steroidogenesis to date, highlighting its modulation in testicular steroidogenesis and its impact on hormone synthesis, follicle development, and fertility therapies.

From barriers to novel strategies: smarter CAR T therapy hits hard to tumors.

Chimeric antigen receptor (CAR) T cell therapy for solid tumors shows promise, but several hurdles remain. Strategies to overcome barriers such as CAR T therapy-related toxicities (CTT), immunosuppression, and immune checkpoints through research and technology are needed to put the last nail to the coffin and offer hope for previously incurable malignancies. Herein we review current literature and infer novel strategies for the mitigation of CTT while impeding immune suppression, stromal barriers, tumor heterogeneity, on-target/off-tumor toxicities, and better transfection strategies with an emphasis on clinical research and prospects.

Gold nanocubes based optical detection of HIV-1 DNA via surface enhanced Raman spectroscopy.

Optical detection of HIV-1 DNA with surface enhanced Raman spectroscopy (SERS) is a quick and versatile method, having great potential in screening and characterization of HIV-1 virus particle. We have synthesized and applied novel gold nanocubes (AuNCs) for signal enhancement of SERS to study HIV-1 DNA strands by taking into account the specific vibrational bands of functional groups. Raman peaks at 562 cm-1, 800 cm-1, 1094 cm-1 were observed in both Human Random Control DNA and HIV-1 DNA, while three new peaks were detected in infected DNA at 421 cm-1, 1069 cm-1 and 1254 cm-1. Raman bands in case of AuNCs coated HIV-1 DNA molecules were observed with enhanced intensity values as compared to the silver nanoparticles-based SERS substrate. In case of silver nanoparticles (AgNPs) conjugate DNA, we get all signatures of HIV-1 virus at almost the same position with peak distortions, peak alterations and intensities reductions. We overall molecularly observed HIV-1 infected DNA and Human Random Control DNA, with high sensitivity and selectivity using highly sensitive and stable AuNCs in SERS. This technique can be utilized to identify molecular structures and chemical identification of biomacromolecules which can further be investigated as biomarkers for the screening of whole-body HIV-1 virus particles.