New-onset seizures: an unusual neurologic manifestation of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory condition primarily affecting the musculoskeletal system but can often involve other organ systems as well. Rheumatoid meningitis is a rare central nervous system (CNS) manifestation of RA characterized by pachymeningeal and leptomeningeal enhancement. Herein, we present a case of a 64-year-old male who presented with left lower extremity weakness and witnessed seizures. The diagnostic work-up, including lumbar puncture, brain MRI and meningeal biopsy ruled out malignancy and were consistent with the diagnosis of rheumatoid meningitis. The patient was discharged on high-dose steroids along with anti-seizure medications. On subsequent follow-up visits, the patient remained seizure-free.

Factors influencing quality of life among the elderly: An approach using logistic regression.

BACKGROUND: Improving the physical, psychological, and social factors in the elderly significantly increases the QoL1 among them. This study aims to identify the crucial factors for predicting QoL among the elderly using statistical methods. MATERIALS AND METHODS: In this study, 980 samples related to the elderly with favorable and unfavorable QoL were investigated. The elderly's QoL was investigated using a qualitative and self-assessment questionnaire that measured the QoL among them by five Likert spectrum and independent factors. The Chi-square test and eta coefficient were used to determine the relationship between each predicting factor of the elderly's QoL in SPSS V 25 software. Finally, we used the Enter and Forward LR methods to determine the correlation of influential factors in the presence of other variables. RESULTS: The study showed that 20 variables gained a significant relationship with the quality of life of the elderly at P < 0.05. The study results showed that the degree of dependence (P = 0.03), diabetes mellitus (P = 0.03), formal and informal social relationships (P = 0.01 and P = 0.02), ability to play an emotional role (P = 0.03), physical performance (P = 0.01), heart diseases and arterial blood pressure (P = 0.02), and cancer (P = 0.01) have favorable predictive power in predicting the QoL among the elderly. CONCLUSION: Attempts to identify and modify the important factors affecting the elderly's QoL have a significant role in improving the QoL and life satisfaction in this age group people. This study showed that the statistical methods have a pleasant capability to discover the factors associated with the elderly's QoL with high performance in this regard.

Clear cell adenocarcinoma of the urinary bladder: a case report and review of literature.

The most common histological type of urinary bladder cancer is urothelial carcinoma (UC). Clear cell adenocarcinoma (CCA) of the urinary bladder is a rare histologic subtype of adenocarcinoma in the urinary tract. The tumor primarily affects women and has histomorphological features resembling CCA of the female genital tract (or Müllerian origin). Clear cell adenocarcinoma consists of cells with abundant clear cytoplasm, arranged in solid, glandular, or tubulocystic patterns. Patients typically present with gross hematuria, dysuria, and discharge. In this study, we report a case of a 50-year-old male, presenting with gross hematuria, which was subsequently diagnosed with CCA at our pathology department. Furthermore, we provide a short systematic review of the literature for this rare histopathological entity and a brief discussion about its morphological and immunohistochemical (IHC) characteristics.

Microsurgical clipping of multiple aneurysms through the unilateral pterional approach via the extended lateral corridor (PAVEL): a case report.

The application of pterional approach via the extended lateral corridor (PAVEL) for aneurysms of the distal basilar artery has been associated with significant successes. However, this approach has been rarely used to manage multiple aneurysms in patients who are not candidates for endovascular intervention. Case presentation: A 58-year-old male patient was referred to our neurosurgical unit with severe headache, nausea and vomiting, and neck pain. The patient had a history of hypertension but no past surgical history. A computerized tomography scan showed subarachnoid hemorrhage in the basal cisterns. Also, three-dimensional cerebral vascular imaging revealed three aneurysms involving the left middle cerebral artery, the basilar artery apex, and the left superior cerebellar artery. Due to his comorbidities and the severity of his symptoms, an endovascular intervention was not possible. The patient underwent the PAVEL approach to clip these three aneurysms. Following surgery, the patient had temporary right-sided hemiparesis and left-side ptosis, which improved 3 months after surgery. Clinical discussion: In this article, we present a narrated video of the intraoperative management of the three aneurysms and discussed the benefit and likely complications of this procedure. Conclusion: The PAVEL approach provides a single approach for multiple anterior and posterior circulation aneurysms instead of multiple procedures, thus minimizing patient postsurgical morbidity and mortality.

Evaluation of expression of biomarkers of PLAGL1 (ZAC1), microRNA, and their non-coding RNAs in patients with endometriosis.

Since the PLAGL1 (ZAC1) gene is expressed in the human endometrium. It may be involved in the etiology of endometrial disorders by its abnormal regulation and expression. This study aimed to investigate the Zac1 gene and related microRNA and LncRNA and its alterations in patients with endometriosis. Blood plasma, ectopic (EC) and eutopic (EU) endometrial samples were gathered from 30 patients with endometriosis and 30 healthy fertile women, and the Q-PCR technique was used to determine the expression level of Zac1 mRNA and microRNAs (miR-1271-5p, hsa-miR-490-3pin) and LncRNAs (TONSL-AS1 TONSL, KCNQ1OT1 KCNQ1). According to the results, the Zac1 gene and KCNQ1OT1 KCNQ1, TONSL-AS1 TONSL LncRNA expression were significantly decreased in the endometriosis group versus the control group (P < 0.05). MiR-1271-5p and hsa-miR-490-3pin microRNA expression were significantly raised in the endometriosis group as opposed to the control group (P < 0.05). In summary, this research for the first time revealed that identifying Zac1 expression provides us with new indicators for evaluating endometriosis.

Impact of Stress on the Immunogenic Potential of Adalimumab.

Monoclonal antibodies against tumor necrosis factor-alpha (TNFα) are widely used for treatment of inflammatory diseases. However, despite the inhibitory effect this class of drugs has on the immune system, anti-drug antibodies are often formed with continuous use. Particles formed during stress conditions, which can be used to simulate storage and handling conditions of commercial antibodies, have previously been associated with the formation of anti-drug antibodies. This study investigates the relationship between particles, oligomerization, folding and chemical degradation on the in vitro cytokine response toward the TNFα inhibitor adalimumab. Adalimumab aggregates generated using stir and heat stress were fractionated into distinct sub-populations, and their structure and immunogenic potential were evaluated. A chemically degraded sample of adalimumab was included to compare particle composition with the milder accelerated heat and stir stressed conditions. Particles from stressed adalimumab samples induced elevated cytokine levels and CD4+ T cell proliferation in vitro compared to non-stressed samples. Samples enriched with both submicron and subvisible particles of adalimumab induced the strongest cytokine release and the strongest CD4+ T cell proliferation despite maintaining some TNFα inhibitory functionality. Samples that were stressed and subsequently purified of subvisible and submicron particles did not elicit a significantly higher cytokine response or show increased CD4+ T cell proliferation compared to a non-stressed sample. Oxidation-induced chemical modifications in adalimumab, mainly in Met, His, Trp, and Tyr, were not found to be sufficient in absence of particle formation to induce increased CD4+ T cell proliferation or cytokine release despite less decreased TNFα inhibitory activity of adalimumab. These observations provide further evidence that particles do indeed potentiate the immunogenic potential of adalimumab.

Supratentorial Meningioma Consistency Prediction Utilizing Tumor to Cerebellar Peduncle Intensity on T1 and T2-Weighted and Fluid Attenuated Inversion Recovery Magnetic Resonance Imaging Sequences.

OBJECTIVE: Predicting meningioma consistency with preoperative imaging is critical for surgery planning. Preoperative T1 and T2-weighted and fluid attenuated inversion recovery magnetic resonance imaging (MRI) findings of supratentorial meningioma tumors were studied and compared with intraoperative supratentorial meningioma tumor consistency based on the Cavitron ultrasound surgical aspirator (CUSA) and ZADA grading scales in this cohort to predict the tumor consistency before surgery. METHODS: MRI from 78 consecutive patients who underwent supratentorial meningioma tumor resection between 2018 and 2021 were evaluated preoperatively. An intraoperative tumor consistency grade was applied to these lesions prospectively by the operating surgeon based on CUSA and ZADA grading scales. Tumor/cerebellar peduncle T2-weighted intensity, tumor/cerebellar peduncle T1-weighted intensity (TCT1I), and tumor/cerebellar peduncle fluid attenuated inversion recovery intensity (TCFI) ratios were calculated. Tumor consistency grades and MRI intensity ratios were correlated using one-way ANOVA. RESULTS: Of the 78 patients, 52 (66.7%) were female and 26 (33.3%) were male. Tumor volume correlated with tumor consistency grades on both CUSA (P = 0.005) and ZADA (P = 0.024) grading scales. Also patients age correlated with tumor consistency according to ZADA grading scale (P = 0.024). TCT1I (P = 0.009) and TCFI (P < 0.005) ratios correlated significantly with tumor consistency grade according to CUSA. Similarly, TCT1I (P = 0.0032) and TCFI (P = 0.001) ratios was significantly associated with tumor consistency according to ZADA grading scales. CONCLUSIONS: Our findings suggest that higher tumor/cerebellar peduncle T2-weighted intensity and TCFI ratios correlate with softer tumors, while higher TCT1I ratios reveal firmer tumors. These data can assist the surgeon predict the supratentorial meningioma consistency before surgery.

Nociceptor neurons affect cancer immunosurveillance.

Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.

Development of a Mobile-Based Self-care Application for Patients with Breast Cancer-Related Lymphedema in Iran.

BACKGROUND: Due to the chronic, progressive, and debilitating nature of breast cancer-related lymphedema (BCRL), it is necessary to observe and maintain self-care management accordingly. This study was conducted to develop a mobile application based on the Android operating system for self-care management of Iranian patients with BCRL. METHODS: An applied developmental study was conducted in 2020. The users' information needs assessment as well as design, development, implementation, and evaluation of the mobile app for self-care management of patients with BCRL was done by searching the literature, reviewing the existing mobile applications, and surveying the users' needs. The mobile app was designed using the Android Studio environment and Java programming language in the Android operating system. The usability of the app was evaluated by 30 patients with BCRL using the questionnaire for user interface satisfaction-seventh version (QUIS 7). RESULTS: The mobile app for BCRL included demographic information, clinical information, lifestyle and system functions (drug use, nutrition, exercise, smoking cessation, communication, and test time reminder). User usability evaluation of the app content and functions confirmed that it was appropriate and satisfactory for the self-management of women with BCRL. CONCLUSION: The mobile app was appropriate in terms of the content, function, and quality for improving the patients' lifestyle and education and self-management of BCRL symptoms according to its usability evaluation from the end-users' (patients) perspective. It is suggested that studies should be performed to confirm the effectiveness and identify the clinical significance of the app.

Teasing Out the Interplay Between Natural Killer Cells and Nociceptor Neurons.

Somatosensory neurons have evolved to detect noxious stimuli and activate defensive reflexes. By sharing means of communication, nociceptor neurons also tune host defenses by controlling the activity of the immune system. The communication between these systems is mostly adaptive, helping to protect homeostasis, it can also lead to, or promote, the onset of chronic diseases. Both systems co-evolved to allow for such local interaction, as found in primary and secondary lymphoid tissues and mucosa. Recent studies have demonstrated that nociceptors directly detect and respond to foreign antigens, immune cell-derived cytokines, and microbes. Nociceptor activation not only results in pain hypersensitivity and itching, but lowers the nociceptor firing threshold, leading to the local release of neuropeptides. The peptides that are produced by, and released from, the peripheral terminals of nociceptors can block the chemotaxis and polarization of lymphocytes, controlling the localization, duration, and type of inflammation. Recent evidence shows that sensory neurons interact with innate immune cells via cell-cell contact, for example, engaging group 2D (NKG2D) receptors on natural killer (NK) cells. Given that NK cells express the cognate receptors for various nociceptor-produced mediators, it is conceivable that nociceptors use neuropeptides to control the activity of NK cells. Here, we devise a co-culture method to study nociceptor neuron-NK cell interactions in a dish. Using this approach, we found that lumbar nociceptor neurons decrease NK cell cytokine expression. Overall, such a reductionist method could be useful to study how tumor-innervating neurons control the anticancer function of NK cells and how NK cells control the elimination of injured neurons.

Does motor control training improve pain and function in adults with symptomatic lumbar disc herniation? A systematic review and meta-analysis of 861 subjects in 16 trials.

OBJECTIVE: To evaluate the effectiveness of motor control training (MCT) compared with other physical therapist-led interventions, minimal/no intervention or surgery in patients with symptomatic lumbar disc herniation (LDH). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Eight databases and the ClinicalTrials.gov were searched from inception to April 2021. ELIGIBILITY CRITERIA: We included clinical trial studies with concurrent comparison groups which examined the effectiveness of MCT in patients with symptomatic LDH. Primary outcomes were pain intensity and functional status which were expressed as mean difference (MD) and standardised mean difference (SMD), respectively. RESULTS: We screened 6695 articles, of which 16 clinical trials (861 participants) were eligible. Fourteen studies were judged to have high risk of bias and two studies had some risk of bias. In patients who did not undergo surgery, MCT resulted in clinically meaningful pain reduction compared with other physical therapist-led interventions (ie, transcutaneous electrical nerve stimulation (TENS)) at short-term (MD -28.85, -40.04 to -17.66, n=69, studies=2). However, the robustness of the finding was poor. For functional status, a large and statistically significant treatment effect was found in favour of MCT compared with traditional/classic general exercises at long-term (SMD -0.83 to -1.35 to -0.31, n=63, studies=1) and other physical therapist-led interventions (ie, TENS) at short-term (SMD -1.43 to -2.41 to -0.46, n=69, studies=2). No studies compared MCT with surgery. In patients who had undergone surgery, large SMDs were seen. In favour of MCT compared with traditional/classic general exercises (SMD -0.95 to -1.32 to -0.58, n=124, studies=3), other physical therapist-led interventions (ie, conventional treatments; SMD -2.30 to -2.96 to -1.64, n=60, studies=1), and minimal intervention (SMD -1.34 to -1.87 to -0.81, n=68, studies=2) for functional improvement at short-term. The overall certainty of evidence was very low to low. CONCLUSION: At short-term, MCT improved pain and function compared with TENS in patients with symptomatic LDH who did not have surgery. MCT improved function compared with traditional/classic general exercises at long-term in patients who had undergone surgery. However, the results should be interpreted with caution because of the high risk of bias in the majority of studies. PROSPERO REGISTRATION NUMBER: CRD42016038166.

Pregnancy-Associated Sacroiliitis following an Uncomplicated Pregnancy.

Pregnancy-associated sacroiliitis is infrequent during the peripartum period. Although pregnancy-associated pyogenic sacroiliitis rarely occurs, it is associated with significant morbidity and mortality. A timely diagnosis of the disease is challenging due to its nonspecific clinical symptoms. We reviewed a case that experienced an acute illness during pregnancy. The illness was manifested by localized pain in the hips or buttocks, sacroiliac joint tenderness, and debilitating hip pain during ambulation. Magnetic resonance imaging revealed little joint involvement, and the patient was treated with antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids. The patient responded well to the therapy with marked improvement in her ambulation. Septic sacroiliitis should be considered in peripartum patients presenting with increased inflammatory markers and severe localized pain. Medical management is usually curative and without an adverse effect on pregnancy. Although we could not perform a biopsy to verify the cause of the disease, the patient's excellent response to the treatment confirmed our diagnosis.

Early Responses to Low-Dose Ionizing Radiation in Cellular Lens Epithelial Models.

Cataract is the leading cause of visual impairment which can result in blindness. Cataract formation has been associated with radiation exposure; however, the mechanistic understanding of this phenomenon is still lacking. The goal of this study was to investigate mechanisms of cataract induction in isolated lens epithelial cells (LEC) exposed to ionizing radiation. Human LECs from different genetic backgrounds (SV40 immortalized HLE-B3 and primary HLEC cells) were exposed to varying doses of 137Cs gamma rays (0, 0.1, 0.25 and 0.5 Gy), at low (0.065 Gy/min) and higher (0.3 Gy/min) dose rates. Different assays were used to measure LEC response for, e.g., viability, oxidative stress, DNA damage studies, senescence and changes to telomere length/telomerase activity at two time points (1 h and 24 h, or 24 h and 15 days, depending on the type of assay and expected response time). The viability of cells decreased in a dose-dependent manner within 24 h of irradiation. Measurement of reactive oxygen species showed an increase at 1 h postirradiation, which was alleviated within 24 h. This was consistent with DNA damage results showing high DNA damage after 1 h postirradiation which reduced significantly (but not completely) within 24 h. Induction of senescence was also observed 15 days postirradiation, but this was not attributed to telomere erosion or telomerase activity reduction. Overall, these findings provide a mechanistic understanding of low-dose radiation-induced cataractogenesis which will ultimately help to inform judgements on the magnitude of risk and improve existing radiation protection procedures.

Desulfurization of liquid fuels using aluminum modified mesoporous adsorbent: towards experimental and kinetic investigations.

In this study, a modified mesoporous adsorbent (MSU-S) impregnated by aluminum was used to remove the aromatic sulfur compounds from n-decane as the model fuel. Physical and chemical properties of as-synthesized adsorbent were investigated by XRD (X-Ray Diffraction), SEM (Scanning Electron Microscopy), FTIR (Fourier Transform Infrared spectroscopy) and BET (Brunauer-Emmett-Teller) method. Adsorptive desulfurization of model fuel was studied through batch and continues processes under mild temperature and normal atmospheric pressure. The equilibrium adsorption was modeled by Langmuir, Temkin, and Freundlich and the kinetics of adsorption was studied through first, second and intraparticle diffusion models. It was figured out that Temkin and the pseudo-second-order model were best fitting the adsorption equilibrium and describing the kinetics, respectively.

Carbohydrate Intake, Glycemic Index, and Glycemic Load and the Risk of Breast Cancer among Iranian Women.

Limited studies have conducted on the association between carbohydrate intake, glycemic index (GI), glycemic load (GL), and BC risk among Middle Eastern women. Our objective was to examine whether intake of carbohydrates, GI and GL would lead to more risk of BC among Iranian women. In this case-control study, 136 women with histologically confirmed BC and 272 control women were recruited. Dietary intake was assessed using a validated 168-item food frequency questionnaire (FFQ) from which GI and GL were estimated. We calculated Odds ratios (OR) using logistic regression. The multivariate OR for the highest vs. the lowest quartile was 2.49 (95% CI 1.28-4.82; P trend = 0.005) for GI with a significant trend. OR for GI and GL among postmenopausal women were 4.45 (95% CI 1.59-12.47; P trend = 0.002) and 4.15 (95% CI 0.87-19.67; P trend = 0.03), respectively. OR for GI among women with reduced vegetable intake was 13.55 (95% CI 3.90-46.99; P trend <0.001). Our data suggest that high GI and GL play an important role in the risk of BC particularly among postmenopausal woman.

The Impact of Mobile Health on Cancer Screening: A Systematic Review.

INTRODUCTION: Mobile health is an emerging technology around the world that can be effective in cancer screening. This study aimed to examine the effectiveness of mobile health applications on cancer screening. METHODS: We conducted a systematic literature review of studies related to the use of mobile health applications in cancer screening. We also conducted a comprehensive search of articles on cancer screening related to the use of mobile health applications in journals published between January 1, 2008, and January 31, 2019, using 5 databases: IEEE, Scopus, Web of Science, Science Direct and PubMed. RESULTS: A total of 23 articles met the inclusion criteria and were included in the present review. All studies have identified positive effects of applications on cancer screening and clinical health outcomes. Furthermore, more than half of mobile applications had multiple functions such as providing information, planning and education. Moreover, most of the studies, which examined the satisfaction of patients and quality improvement, showed healthcare application users have significantly higher satisfaction of living and it leads to improving quality. CONCLUSION: This study found that the use of mobile health applications has a positive impact on health-related behaviours and outcomes. Application users were more satisfied with applying mobile health applications to manage their health condition in comparison with users who received conventional care.

Common data elements of breast cancer for research databases: A systematic review.

BACKGROUND: Common Data Elements (CDEs) are data-metadata descriptors used to collect research study data. CDEs facilitate the collection, processing, and sharing of breast cancer data. This study intended to explore the CDEs of breast cancer for research databases and primary care systems. METHODS: This study was conducted using systematic search and review. This systematic literature review covered PubMed, Scopus, Science Direct, SID, ISC, Web of Science, and Google Scholar search engine. It included studies in English language with accessible full-text from the beginning of 2007 to September 2019. RESULTS: Reviewing 25 studies revealed that 52 percent of studies were carried out in the US and most studies were conducted between 2013 and 2015. The most domains for using CDEs were: Pathology Report and Registry. The CDEs of breast cancer for research databases were categorized into three categories namely clinical, research, and non-clinical and indicate the importance of these data elements. Most of the studies focused on creating and deploying clinical CDEs as physical examination, clinical history and pathology data. CONCLUSION: The integration of biomedical and clinical data relevant to breast cancer enhances the power of research variable analysis and statistical analysis, thereby facilitating improved knowledge of effective therapeutic interventions. Also CDEs used to collect, store, and retrieve patient data in various health setting such as primary care and research databases.

A Novel Sulfonyl-Based Small Molecule Exhibiting Anti-cancer Properties.

Phenotypic screening is an ideal strategy for the discovery of novel bioactive molecules. Using a customized high-throughput screening (HTS) assay employing primary T lymphocytes, we screened a small library of 4,398 compounds with unknown biological function/target to identify compounds eliciting immunomodulatory properties and discovered a sulfonyl-containing hit, we named InhiTinib. This compound inhibited interferon (IFN)-gamma production and proliferation of primary CD3+ T cells without inducing cell death. In contrast, InhiTinib triggered apoptosis in several murine and human cancer cell lines. Besides, the compound was well tolerated by immunocompetent mice, triggered tumor regression in animals with pre-established EL4 T-cell lymphomas, and prolonged the overall survival of mice harboring advanced tumors. Altogether, our data demonstrate the anti-cancer properties of InhiTinib, which can henceforth bridge to wider-scale biochemical and clinical tests following further in-depth pharmacodynamic studies.

Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy.

Diabetes is a common condition characterized by persistent hyperglycemia. High blood sugar primarily affects cells that have a limited capacity to regulate their glucose intake. These cells include capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, Schwann cells, and neurons of the peripheral and central nervous systems. As a result, hyperglycemia leads to largely intractable complications such as retinopathy, nephropathy, hypertension, and neuropathy. Diabetic pain neuropathy is a complex and multifactorial disease that has been associated with poor glycemic control, longer diabetes duration, hypertension, advanced age, smoking status, hypoinsulinemia, and dyslipidemia. While many of the driving factors involved in diabetic pain are still being investigated, they can be broadly classified as either neuron -intrinsic or -extrinsic. In neurons, hyperglycemia impairs the polyol pathway, leading to an overproduction of reactive oxygen species and reactive nitrogen species, an enhanced formation of advanced glycation end products, and a disruption in Na+/K+ ATPase pump function. In terms of the extrinsic pathway, hyperglycemia leads to the generation of both overactive microglia and microangiopathy. The former incites a feed-forward inflammatory loop that hypersensitizes nociceptor neurons, as observed at the onset of diabetic pain neuropathy. The latter reduces neurons' access to oxygen, glucose and nutrients, prompting reductions in nociceptor terminal expression and losses in sensation, as observed in the later stages of diabetic pain neuropathy. Overall, microglia can be seen as potent and long-lasting amplifiers of nociceptor neuron activity, and may therefore constitute a potential therapeutic target in the treatment of diabetic pain neuropathy.