Prevalence of autoimmune diseases in functional neurological disorder: influence of psychiatric comorbidities and biological sex.

BACKGROUND: Functional neurological disorder (FND) is a common and disabling neuropsychiatric condition, which disproportionally affects women compared with men. While the etiopathogenesis of this disorder remains elusive, immune dysregulation is emerging as one potential mechanism. To begin to understand the role of immune dysfunctions in FND, we assessed the prevalence of several common autoimmune diseases (ADs) in a large cohort of patients with FND and examined the influence of psychiatric comorbidities and biological sex. METHODS: Using a large biorepository database (Mass General Brigham Biobank), we obtained demographic and clinical data of a cohort of 643 patients diagnosed with FND between January 2015 and December 2021. The proportion of ADs was calculated overall, by sex and by the presence of psychiatric comorbidities. RESULTS: The overall prevalence of ADs in our sample was 41.9%, with connective tissue and autoimmune endocrine diseases being the most commonly observed ADs. Among patients with FND and ADs, 27.7% had ≥2 ADs and 8% met criteria for multiple autoimmune syndrome. Rates of ADs were significantly higher in subjects with comorbid major depressive disorder and post-traumatic stress disorder (p= 0.02). Women represented the largest proportion of patients with concurrent ADs, both in the overall sample and in the subgroups of interest (p's < 0.05). CONCLUSIONS: This study is unique in providing evidence of an association between FND and ADs. Future studies are needed to investigate the mechanisms underlying this association and to understand whether FND is characterised by distinct dysregulations in immune response.

State-of-the-Art Review on Wearable Obstacle Detection Systems Developed for Assistive Technologies and Footwear.

Walking independently is essential to maintaining our quality of life but safe locomotion depends on perceiving hazards in the everyday environment. To address this problem, there is an increasing focus on developing assistive technologies that can alert the user to the risk destabilizing foot contact with either the ground or obstacles, leading to a fall. Shoe-mounted sensor systems designed to monitor foot-obstacle interaction are being employed to identify tripping risk and provide corrective feedback. Advances in smart wearable technologies, integrating motion sensors with machine learning algorithms, has led to developments in shoe-mounted obstacle detection. The focus of this review is gait-assisting wearable sensors and hazard detection for pedestrians. This literature represents a research front that is critically important in paving the way towards practical, low-cost, wearable devices that can make walking safer and reduce the increasing financial and human costs of fall injuries.

Infections following rejection therapies in kidney and liver transplant recipients.

INTRODUCTION: Infections are known complications of solid-organ transplant. Treatment for rejection may increase risk of infection. We aimed to study frequency of infection and identify the risk factors for infections in solid organ transplant (SOT) (liver and kidney) recipients treated for rejection. METHODS: This is a retrospective chart review of all liver and kidney transplant recipients treated for rejection at our institution from 2014 to 2020. We collected information on episodes of acute rejection in the first year of transplant and infections within 6 months following rejection treatment. RESULTS: We identified 257 transplant patients treated for rejection. One hundred twelve (43.6%) developed infections, with a total of 226 infections. Urinary tracts infections were the most common, 72 (31.9%), followed by cytomegalovirus viremia in 37 (16.4%), bacteremia in 24 (10.6%), and BK virus in 14 (6.2%). Female sex (p = .047), elevated neutrophil count at rejection (p = .002), and increased number of rejection episodes (p = .022) were predictors of infection in kidney and simultaneous liver-kidney recipients. No specific type of induction or rejection therapy was identified as a risk factor for infection, likely due to the prophylaxis protocols at our institution. Infection post rejection treatment was associated with higher graft loss (p = .021) and mortality (p = .031) in kidney transplant recipients. CONCLUSIONS: Infections are common complications after treatment of SOT rejection. Female gender, higher neutrophil at time of rejection, and increased numbers of rejection episodes were predictors of infections after rejection in simultaneous liver-kidney and kidney transplant patients. Infections were predictors of graft loss at 6 months and mortality at any point in follow-up in kidney transplant patients.

Robotic-Assisted Total Knee Arthroplasty Allows for Trainee Involvement and Teaching Without Lengthening Operative Time.

BACKGROUND: Robot-assisted total knee arthroplasty (RA-TKA) is more accurate than mechanical total knee arthroplasty (M-TKA) and can provide real-time feedback about alignment and soft-tissue balancing that may be helpful in trainee education. However, both robotic-assist and trainee involvement potentially increase the surgical time. This study sought to evaluate whether RA-TKA procedures were longer than M-TKA procedures and whether trainee participation added additional surgical time. METHODS: This retrospective cohort study reviewed 220 consecutive primary TKAs (110 M-TKA and 110 RA-TKA) performed by an orthopedic trainee under supervision or performed by the consultant surgeon with an assistant present. For M-TKAs, a measured resection technique was used. For all RA-TKAs, the MAKO robotic system (Stryker, USA) was used. Tourniquet time was measured from inflation immediately prior to skin incision to deflation after placement of the final polyethylene insert. Procedures performed by a consulting surgeon with a surgical assist were used as controls for procedures performed by the trainee. In trainee-conducted procedures, the trainee is responsible for performing all critical aspects of the procedure while the consulting surgeon provides supervision and acts as first assist. RESULTS: 103 M-TKA and 96 RA-TKA were included. Tourniquet time was significantly longer for RA-TKAs vs M-TKAs (100 vs 89 minutes, P < .0001). However, there were no significant differences in tourniquet times between surgery performed by a trainee vs the consulting surgeon with surgical assist for either M-TKA (P = .3452) or RA-TKA (P = .6724). CONCLUSIONS: While RA-TKA takes longer, orthopedic trainees do not add additional time. Trainees at all stages of postgraduate learning can be educated in the use of robotic technology and potentially benefit from real-time feedback without further compromising surgical efficiency or increasing patient risk.

Application of Wearable Sensors in Actuation and Control of Powered Ankle Exoskeletons: A Comprehensive Review.

Powered ankle exoskeletons (PAEs) are robotic devices developed for gait assistance, rehabilitation, and augmentation. To fulfil their purposes, PAEs vastly rely heavily on their sensor systems. Human-machine interface sensors collect the biomechanical signals from the human user to inform the higher level of the control hierarchy about the user's locomotion intention and requirement, whereas machine-machine interface sensors monitor the output of the actuation unit to ensure precise tracking of the high-level control commands via the low-level control scheme. The current article aims to provide a comprehensive review of how wearable sensor technology has contributed to the actuation and control of the PAEs developed over the past two decades. The control schemes and actuation principles employed in the reviewed PAEs, as well as their interaction with the integrated sensor systems, are investigated in this review. Further, the role of wearable sensors in overcoming the main challenges in developing fully autonomous portable PAEs is discussed. Finally, a brief discussion on how the recent technology advancements in wearable sensors, including environment-machine interface sensors, could promote the future generation of fully autonomous portable PAEs is provided.

A Detailed Characterization of the Dysfunctional Immunity and Abnormal Myelopoiesis Induced by Severe Shock and Trauma in the Aged.

The elderly are particularly susceptible to trauma, and their outcomes are frequently dismal. Such patients often have complicated clinical courses and ultimately die of infection and sepsis. Recent research has revealed that although elderly subjects have increased baseline inflammation as compared with their younger counterparts, the elderly do not respond to severe infection or injury with an exaggerated inflammatory response. Initial retrospective analysis of clinical data from the Glue Grant trauma database demonstrated that despite a similar frequency, elderly trauma patients have worse outcomes to pneumonia than younger subjects do. Subsequent analysis with a murine trauma model also demonstrated that elderly mice had increased mortality after posttrauma Pseudomonas pneumonia. Blood, bone marrow, and bronchoalveolar lavage sample analyses from juvenile and 20-24-mo-old mice showed that increased mortality to trauma combined with secondary infection in the aged are not due to an exaggerated inflammatory response. Rather, they are due to a failure of bone marrow progenitors, blood neutrophils, and bronchoalveolar lavage cells to initiate and complete an emergency myelopoietic response, engendering myeloid cells that fail to clear secondary infection. In addition, elderly people appeared unable to resolve their inflammatory response to severe injury effectively.

Extranodal Non-Hodgkin's Lymphoma of the Oral Cavity: A Case Report.

Lymphomas are solid malignant tumors having a wide spectrum of clinical and pathological features. Non-Hodgkin's lymphoma (NHL) is a subtype of lymphoma with two-thirds of the cases presenting as lymph node enlargement. The remaining one third of NHL cases has been reported in the extranodal sites, including the gastro intestinal tract, Waldeyer's ring, bone, skin, and brain. Intraoral non-Hodgkin's lymphoma is uncommon and may affect either the jaw bones or occur within the soft tissues of the oral cavity. Here we report a case of non-Hodgkin's lymphoma in a 65-year-old male patient who presented with a growth from the extraction socket. Non-Hodgkin's lymphoma presenting as a growth from the extraction socket is unusual. An orthopantamograph (OPG) was taken which revealed a diffuse radiolucent defect in relation to the extraction socket of the left lower molar region. Routine hemogram, urine analysis, and chest radiograph were normal. Incisional biopsy was performed and the tissue was subjected to histopathological examination. Histopathological and immunohistochemical analysis confirmed the diagnosis of B-cell lymphoma. The patient was referred to a regional cancer institute for further management, where chemotherapy was planned. However, prior to chemotherapy, the patient was diagnosed with brain metastasis and he expired in hospital within one month.

Beneficial effects of exercise on age-related mitochondrial dysfunction and oxidative stress in skeletal muscle.

Mitochondria are negatively affected by ageing leading to their inability to adapt to higher levels of oxidative stress and this ultimately contributes to the systemic loss of muscle mass and function termed sarcopenia. Since mitochondria are central mediators of muscle health, they have become highly sought-after targets of physiological and pharmacological interventions. Exercise is the only known strategy to combat sarcopenia and this is largely mediated through improvements in mitochondrial plasticity. More recently a critical role for mitochondrial turnover in preserving muscle has been postulated. Specifically, cellular pathways responsible for the regulation of mitochondrial turnover including biogenesis, dynamics and autophagy may become dysregulated during ageing resulting in the reduced clearance and accumulation of damaged organelles within the cell. When mitochondrial quality is compromised and homeostasis is not re-established, myonuclear cell death is activated and muscle atrophy ensues. In contrast, acute and chronic exercise attenuates these deficits, restoring mitochondrial turnover and promoting a healthier mitochondrial pool that leads to the preservation of muscle. Additionally, the magnitude of these exercise-induced mitochondrial adaptations is currently debated with several studies reporting a lower adaptability of old muscle relative to young, but the processes responsible for this diminished training response are unclear. Based on these observations, understanding the molecular details of how advancing age and exercise influence mitochondria in older muscle will provide invaluable insight into the development of exercise protocols that will maximize beneficial adaptations in the elderly. This information will also be imperative for future research exploring pharmacological targets of mitochondrial plasticity.

Protective immunity and defects in the neonatal and elderly immune response to sepsis.

Populations encompassing extremes of age, including neonates and elderly, have greater mortality from sepsis. We propose that the increased mortality observed in the neonatal and elderly populations after sepsis is due to fundamental differences in host-protective immunity and is manifested at the level of the leukocyte transcriptome. Neonatal (5-7 d), young adult (6-12 wk), or elderly (20-24 mo) mice underwent a cecal slurry model of intra-abdominal sepsis. Both neonatal and elderly mice exhibited significantly greater mortality to sepsis (p < 0.05). Neonates in particular exhibited significant attenuation of their inflammatory response (p < 0.05), as well as reductions in cell recruitment and reactive oxygen species production (both p < 0.05), all of which could be confirmed at the level of the leukocyte transcriptome. In contrast, elderly mice were also more susceptible to abdominal peritonitis, but this was associated with no significant differences in the magnitude of the inflammatory response, reduced bacterial killing (p < 0.05), reduced early myeloid cell activation (p < 0.05), and a persistent inflammatory response that failed to resolve. Interestingly, elderly mice expressed a persistent inflammatory and immunosuppressive response at the level of the leukocyte transcriptome, with failure to return to baseline by 3 d. This study reveals that neonatal and elderly mice have profoundly different responses to sepsis that are manifested at the level of their circulating leukocyte transcriptome, although the net result of increased mortality is similar. Considering these differences are fundamental aspects of the genomic response to sepsis, interventional therapies will require individualization based on the age of the population.

A comparison among the tissue-specific effects of aging and calorie restriction on TFAM amount and TFAM-binding activity to mtDNA in rat.

BACKGROUND: Mitochondrial Transcription Factor A (TFAM) is regarded as a histone-like protein of mitochondrial DNA (mtDNA), performing multiple functions for this genome. Aging affects mitochondria in a tissue-specific manner and only calorie restriction (CR) is able to delay or prevent the onset of several age-related changes also in mitochondria. METHODS: Samples of the frontal cortex and soleus skeletal muscle from 6- and 26-month-old ad libitum-fed and 26-month-old calorie-restricted rats and of the livers from 18- and 28-month-old ad libitum-fed and 28-month-old calorie-restricted rats were used to detect TFAM amount, TFAM-binding to mtDNA and mtDNA content. RESULTS: We found an age-related increase in TFAM amount in the frontal cortex, not affected by CR, versus an age-related decrease in the soleus and liver, fully prevented by CR. The semi-quantitative analysis of in vivo binding of TFAM to specific mtDNA regions, by mtDNA immunoprecipitation assay and following PCR, showed a marked age-dependent decrease in TFAM-binding activity in the frontal cortex, partially prevented by CR. An age-related increase in TFAM-binding to mtDNA, fully prevented by CR, was found in the soleus and liver. MtDNA content presented a common age-related decrease, completely prevented by CR in the soleus and liver, but not in the frontal cortex. CONCLUSIONS: The modulation of TFAM expression, TFAM-binding to mtDNA and mtDNA content with aging and CR showed a trend shared by the skeletal muscle and liver, but not by the frontal cortex counterpart. GENERAL SIGNIFICANCE: Aging and CR appear to induce similar mitochondrial molecular mechanisms in the skeletal muscle and liver, different from those elicited in the frontal cortex.

Increased inflammation but similar physical composition and function in older-aged, HIV-1 infected subjects.

BACKGROUND: Systemic immune activation (inflammation) and immunosenescence develop in some people with advancing age. This process, known as "inflamm-aging," is associated with physical frailty and sarcopenia. Meanwhile, successful antiretroviral therapy has led to a growing number of older HIV-1-infected individuals who face both age-related and HIV-1-related inflammation, which may synergistically promote physical decline, including frailty and sarcopenia. The purpose of our study was to determine if inflammation during treated HIV-1 infection worsens physical impairment in older individuals. METHODS: We determined the severity of HIV-associated inflammation and physical performance (strength and endurance) in 21 older HIV-infected individuals (54-69 years) receiving suppressive antiretroviral therapy, balanced for confounding variables including age, anthropometrics, and co-morbidities with 10 uninfected control individuals. Biomarkers for microbial translocation (lipopolysaccharide [LPS]), inflammation (soluble CD14 [sCD14], osteopontin, C-reactive protein [CRP], interleukin-6 [IL-6], soluble ICAM-1 [sICAM-1] and soluble VCAM-1 [sVCAM-1]), and coagulopathy (D-dimer) were assayed in plasma. Activation phenotypes of CD4(+)T cells, CD8(+) T cells and monocytes were measured by flow cytometry. Physical performance was measured by 400 m walking speed, a short physical performance battery [SPPB], and lower extremity muscle strength and fatigue. RESULTS: Overall physical function was similar in the uninfected and HIV-infected groups. Compared to uninfected individuals, the HIV-infected group had elevated levels of sCD14 (P < 0.001), CRP (P < 0.001) and IL-6 (P = 0.003) and an increased frequency of CD4(+) and CD8(+) T cells with an immunosenescent CD57(+) phenotype (P = 0.004 and P = 0.043, respectively). Neither plasma inflammatory biomarkers nor CD57(+) T cells correlated with CD4(+) T cell counts. Furthermore, none of the elevated inflammatory biomarkers in the HIV-infected subjects were associated with any of the physical performance results. CONCLUSIONS: When age-related co-morbidities were carefully balanced between the uninfected and HIV-infected groups, no evidence of inflammation-associated physical impairment was detected. Despite careful balancing for age, BMI, medications and co-morbidities, the HIV-infected group still displayed evidence of significant chronic inflammation, including elevated sCD14, CRP, IL-6 and CD57(+) T cells, although the magnitude of this inflammation was unrelated to physical impairment.

Effect of intermittent phrenic nerve stimulation during cardiothoracic surgery on mitochondrial respiration in the human diaphragm.

OBJECTIVES: Recent studies have shown that brief periods of mechanical ventilation in animals and humans can lead to ventilator-induced diaphragmatic dysfunction, which includes muscle atrophy, reduced force development, and impaired mitochondrial function. Studies in animal models have shown that short periods of increased diaphragm activity during mechanical ventilation support can attenuate ventilator-induced diaphragmatic dysfunction but corresponding human data are lacking. The purpose of this study was to examine the effect of intermittent diaphragm contractions during cardiothoracic surgery, including controlled mechanical ventilation, on mitochondrial respiration in the human diaphragm. DESIGN: Within subjects repeated measures study. SETTING: Operating room in an academic health center. PATIENTS: Five subjects undergoing elective cardiothoracic surgery. INTERVENTIONS: In patients (age 65.6 ± 6.3 yr) undergoing cardiothoracic surgery, one phrenic nerve was stimulated hourly (30 pulses/min, 1.5 msec duration, 17.0 ± 4.4 mA) during the surgery. Subjects received 3.4 ± 0.6 stimulation bouts during surgery. Thirty minutes following the last stimulation bout, samples of diaphragm muscle were obtained from the anterolateral costal regions of the stimulated and inactive hemidiaphragms. MEASUREMENTS AND MAIN RESULTS: Mitochondrial respiration was measured in permeabilized muscle fibers with high-resolution respirometry. State III mitochondrial respiration rates (pmol O2/s/mg wet weight) were 15.05 ± 3.92 and 11.42 ± 2.66 for the stimulated and unstimulated samples, respectively (p < 0.05). State IV mitochondrial respiration rates were 3.59 ± 1.25 and 2.11 ± 0.97 in the stimulated samples and controls samples, respectively (p < 0.05). CONCLUSION: These are the first data examining the effect of intermittent contractions on mitochondrial respiration rates in the human diaphragm following surgery/mechanical ventilation. Our results indicate that very brief periods (duty cycle ~1.7%) of activity can improve mitochondrial function in the human diaphragm following surgery/mechanical ventilation.

Identification and Evaluation of Cancer Stem Cells in Oral Squamous Cell Carcinoma and Oral Epithelial Dysplasia Using NANOG: An Immunohistochemical Study.

BACKGROUND: Squamous cell carcinoma of the oral cavity may show precursor lesions, termed as potentially malignant disorders, of which leukoplakia is the most frequent one. Oral leukoplakia is a clinical diagnosis for which the histological diagnosis may be either hyperplasia or oral epithelial dysplasia (OED) and sometimes even oral squamous cell carcinoma (OSCC). Cancer stem cells (CSCs), identified in various tumors, are a specific group of cells that exhibit the properties of self-renewal and differentiation. Among the various biomarkers that identify CSCs, the transcription factor NANOG is considered to be a significant one. AIM: In this study, we intend to identify and compare the immunohistochemical expression of NANOG in OSCC, OED, and normal oral mucosa. METHODOLOGY: Tissue blocks of OSCC (n=28), OED (n=28), and normal oral mucosa (n=28) were used in this study. Specimens were immunohistochemically analyzed for NANOG expression. The results were statistically analyzed using one-way ANOVA, Games-Howell post hoc, and Student t-test. Statistical Product and Service Solutions (SPSS, version 21; IBM SPSS Statistics for Windows, Armonk, NY) software was used for performing the statistical analysis, and the level of significance was set as 0.05. OBSERVATIONS: NANOG expression was higher in OSCC when compared to oral dysplasias and normal oral mucosa, in decreasing order. A significantly higher histo-score and labeling index score were observed in OSCC and oral dysplasias compared to normal oral mucosa (p=<0.001). CONCLUSION: The expression levels of NANOG were positively correlated with disease progression in OSCC, implicating that NANOG can be used as a surrogate marker of oral oncogenesis and prognosis. Therefore, decoding the molecular mechanisms of NANOG regulation in the progression of cancer helps in developing new therapeutic strategies for oral cancer.

Evaluation of Cytotoxic T Lymphocytes and Natural Killer Cell Distribution in Oral Squamous Cell Carcinoma and Oral Epithelial Dysplasia: An Immunohistochemical Study.

Background The tumor microenvironment comprises stromal cells, a few immune cells, vascular channels, and an extracellular matrix. The immune cells play a pivotal role in arresting the development of various tumors by identifying and killing the abnormal tumor cells. These immune cells with cytotoxic function include the natural killer (NK) cells and CD8+ T lymphocytes. Human NK cells express the cell surface marker CD57 and can be identified by using monoclonal antibodies. CD8+ cytotoxic T cells are a critical subpopulation of T cells and are important mediators of adaptive immunity. The anti-tumor immunity is important to assess the prognosis of tumors and develop new therapies. This study aimed to evaluate the immunohistochemical expression of CD8 and CD57 immune cells in oral squamous cell carcinoma (OSCC), oral epithelial dysplasia (OED), and normal oral mucosa. Methodology Clinically diagnosed and histopathologically confirmed cases of OSCC (n = 22), oral leukoplakia with OED (n = 22), and normal oral mucosa (n = 22) comprised the study groups. The tissue sections were subjected to immunohistochemical analysis for CD8 and CD57 expression by calculation of the mean labeling index. The results were statistically analyzed using a one-way analysis of variance, Bonferroni multiple comparison test, and Student's t-test. SPSS software version 20.0 (IBM Corp., Armonk, NY, USA) was used for the statistical analysis, and the significance level was set at 0.05. Results An overall statistically significant difference was obtained in the number of CD8+ T lymphocyte cells and CD57+ NK cells when compared between OSCC, OED, and normal oral mucosa (p = 0.01). Variations in the number of CD8+ T lymphocyte cells and CD57+ NK cells were observed when a comparison was made between OED and OSCC and between OSCC and normal mucosal samples (p = 0.01). The study results showed that the mean labeling index of CD8 and CD57 increased in OSCC when compared to OED and normal mucosa (p = 0.01). Conclusions Samples of OED with moderate or severe dysplasia and samples of OSCC were accompanied by a higher level of infiltrating immune cells such as T cells, B cells, NK cells, and macrophages when compared to normal mucosa. The results suggested that the expression of CD8 and CD57 cells increased from normal mucosa to OED and the highest expression was found in OSCC. CD8 and CD57 could be used as surrogate markers to assess the malignant potential of the lesion and to determine the prognosis of patients with oral cancer.

Preoperative Postvoid Residual Is Not Predictive of Postoperative Urinary Retention in Primary Total Joint Arthroplasty Patients.

Background: Postoperative urinary retention is a common complication after total hip and knee arthroplasty. Postvoid residual (PVR) scanning is a noninvasive method commonly used to evaluate this complication. Preoperatively increased PVR (PrePVR) has been suggested as a risk factor for postoperative catheterization. The aim of this study was to prospectively assess the importance of PrePVR and its relationship with urinary catheter placement, urology consult, and length of stay postoperatively. Methods: Data was prospectively and consecutively collected at a single institution. All patients were bladder scanned preoperatively to collect PrePVR and subsequently scanned on postoperative days zero and one to collect Postoperative PVR. Chart review was performed to determine the number of straight catheterizations, Foley placement, urology consult and length of stay as well as patient demographics. Results: Ninety-four consecutive patients were included in this study. There was a significantly increased postoperative PVR as compared to PrePVR (48.0 mL vs 21.0 mL; P < .0001). A PrePVR >50 mL was not associated with a significant difference in PVR between before and after surgery (P = .13); length of stay (P = .08); need for straight catheterization (P = .11); postoperative Foley placement (P = 1.0); or urology consult (P = 1.0). The only significant risk factor identified for postoperative Foley catheter placement was age (77.7 vs 64.2; P = .02). Conclusions: PrePVR >50 mL was not an accurate predictor of postoperative urinary retention after total joint arthroplasty. PVR significantly increased in all patients. Male sex and increasing age were associated with large increases in PVR postoperatively and an increased risk of catheterization.

Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy.

Muscle loss during aging and disuse is a highly prevalent and disabling condition, but knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and muscle atrophy. Damaged mitochondria are not only less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display a greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, which suggests that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such a network will likely provide clinicians with novel and highly effective therapeutics to counter the muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions.

Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse.

INTRODUCTION: The mitochondrial network within cells is mediated by fission and fusion processes. METHODS: We investigated the expression of the proteins responsible for these events during conditions of altered oxidative capacity. RESULTS: With chronic contractile activity, the mitochondrial reticulum increased in size, along with concomitant increases in the fusion proteins Opa1 and Mfn2 (by 36% and 53%; P < 0.05). When we induced muscle disuse through denervation for 7 days, fragmented mitochondria were observed, along with significant decreases in the expression of Mfn2 and Opa1 (by 84% and 70%). To assess the effects of aging on mitochondrial morphology, young (5 month) and aged (35 month) Fisher 344 Brown Norway rats were used. Aged animals also possessed smaller mitochondria and displayed increased levels of fission proteins. CONCLUSIONS: Chronic muscle use increases the ratio of fusion:fission proteins, leading to reticular mitochondria, whereas muscle disuse and aging result in a decrease in this ratio, culminating in fragmented organelles.

Epithelial-mesenchymal transition in cancer stem cells: Therapeutic implications.

Cancer stem cells (CSCs) are cancer cells that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs may generate tumors through the processes of self-renewal and differentiation into multiple cell types. CSCs present in tumors are normally resistant to conventional therapy and may contribute to tumor recurrence. Tumor residuals present after therapy, with CSCs enrichment, have all the hallmarks of epithelial-mesenchymal transition (EMT). In this review, we discuss the relationship between EMT and CSCs in cancer progression and its therapeutic implications in oral squamous cell carcinoma.

Correlation of PD-1 and PD-L1 expression in oral leukoplakia and oral squamous cell carcinoma: an immunohistochemical study.

The programmed cell death protein (PD-1)/programmed cell death protein ligand (PD-L1) pathway and cytotoxic T lymphocyte antigen are the most important co-stimulatory molecules that play a key role in the negative regulation of T cells during carcinogenesis. We aimed to evaluate the immunohistochemical expression of PD-1 and PD-L1 in oral leukoplakia and squamous cell carcinoma compared with normal oral mucosa. Twenty-five cases of oral squamous cell carcinoma, oral leukoplakia and normal oral mucosa tissue specimens were immunohistochemically stained to assess PD-1 and PD-L1 expression. The PD-L1 positivity of subepithelial TAFs (p < 0.001) increased with increasing grades of oral leukoplakia. Pearson's correlation indicated a high positive correlation between the PD-L1 labelling index of epithelial tumour cells and the PD-1 labelling index of tumour infiltrating lymphocytes (p value: 0.005) in OSCC. A high positive correlation was noted between the H-score of PD-L1 positive tumour epithelial cells and the H-score of PD-1 positive tumour infiltrating lymphocytes in OSCC (p value: 0.001). PD-L1 positivity increased in dysplastic epithelial cells from premalignant lesions to malignancy. The sub-epithelial PD-L1 positive TAFs were higher in oral leukoplakia compared to OSCC inferring that PD-L1 positivity in TAFs decreased with malignant transformation. The PD-1 positivity in TILs was higher in oral leukoplakia than in OSCC.

Significance of tumour budding and invasive characteristics in grading of oral squamous cell carcinoma.

Background: Tumour budding has been recognized as a morphologic marker of tumour invasion. Invasive characteristics such as depth of invasion, mode of invasion and worst pattern of invasion are potentially powerful parameters predicting the regional metastasis. Aim: This study was done to understand the significance of tumour budding and various characteristics of invasion and their impact on grading of oral squamous cell carcinoma. Materials and Methods: An immunohistochemical study was performed on tissue sections obtained from 34 paraffin-embedded blocks of clinically and histologically diagnosed cases of oral squamous cell carcinoma. The sections were stained with pan cytokeratin and observed under high power magnification. Results: Tumour budding and the invasive patterns were found to be significant in OSCC. A proposed grading system based on tumour budding and cell nest was found to have a significant correlation with the WHO grading system. Conclusion: This study demonstrated the importance of using tumour buds as an additional parameter in the grading system and also assessed the importance of invasive patterns, cellular atypia and stromal contents in OSCC.