TSH levels within the normal range and risk of cardiovascular and all-cause mortality among individuals with diabetes.

BACKGROUND: Evidence regarding thyroid-stimulating hormone (TSH) levels within the normal range and mortality in adults with diabetes is scarce. This study aimed to identify the association between TSH levels and cardiovascular disease (CVD) and all-cause mortality among euthyroid patients with diabetes. METHODS: This prospective cohort study included 1830 adults with diabetes from the Third National Health and Nutrition Examination Survey III. Mortality outcomes were ascertained by linkage to National Death Index records through December 31, 2019. Participants were categorized by tertiles of TSH levels (low-normal, 0.39-1.30 mIU/L; medium-normal, 1.30-2.09 mIU/L; high-normal, 2.09-4.60 mIU/L). Multivariable Cox proportional hazards models were used to explore the association between TSH levels within the normal range and overall and CVD mortality. Furthermore, restricted cubic spline analyses were used to determine the nonlinear relationship between TSH levels and mortality. RESULTS: During a median follow-up of 17.1 years, 1324 all-cause deaths occurred, including 525 deaths from CVD. After multivariate adjustment, a U-shaped relationship was observed between TSH levels in euthyroid status and all-cause or CVD mortality among patients with diabetes (both P < 0.05 for nonlinearity). Compared with participants with medium-normal TSH levels, those with high-normal TSH levels had a significantly higher risk of all-cause (hazard ratio, 1.31; 95% confidence interval, 1.07-1.61) and CVD (1.52; 1.08-2.12) mortality. Similarly, low-normal TSH levels also increased all-cause (1.39; 1.12-1.73) and CVD (1.69; 1.17-2.44) mortality risk. In stratum-specific analyses, we found that high-normal TSH levels were associated with higher mortality risk in younger (< 60 years) patients with diabetes but not in older (≥ 60 years) participants. CONCLUSION: Low- and high-normal serum TSH levels were associated with increased all-cause and CVD mortality in euthyroid adults with diabetes. Further studies are needed to confirm the present observation in a wider population.

Are the shoreline and eutrophication of desert lakes related to desert development?

Desert lakes are unique ecosystems found in oases within desert landscapes. Despite the numerous studies on oases, there are no reports regarding the spatiotemporal distribution and causes of eutrophication in the desert lakes that are located at the edge of the Linze Oasis in northwestern China. In this study, the seasonal shoreline and eutrophication of a desert lake were monitored using an unmanned aerial vehicle (UAV) and water sampling during three crop growth stages. The spatial extents of the shoreline and algal blooms and the chromophoric dissolved organic matter (CDOM) absorption coefficient were derived through UAV images. The desert lake shoreline declined during the crop growing stage, which exhibited the largest water demand and began to expand after this stage. The estimated CDOM absorption coefficient measurements and classified algal bloom area showed seasonal variations that increased from spring to late summer and then decreased in autumn. The first two crop growth stages accounted for most of the water and fertilizer requirements of the entire growth period, which may have contributed to large amounts of groundwater consumption and pollution and resulted in peak eutrophication of the lake in the second growth stage. However, the CDOM absorption coefficient of the third stage was not well correlated with that of the first two stages, suggesting that the lake may be affected by the dual effects of groundwater and precipitation recharge in the third stage. These results indicate that the water quality of desert lakes may be affected by agricultural cultivation. The agricultural demands for water and fertilizer may change the spatiotemporal changes in water quality in the lake, especially in the middle and early stages of crop growth.

Sand fixation and human activities on the Qinghai-Tibet Plateau for ecological conservation and sustainable development.

The sand fixation ecosystem services and human activities on the Qinghai-Tibet Plateau (QTP) play a crucial role in local sustainable development and ecosystem health, with significant implications for surrounding regions and the global ecological environment. We employed an improved integrated wind erosion modeling system (IWEMS) model for the QTP to simulate sand fixation quantities under the unique low temperature and low pressure conditions prevalent on the plateau. Using the human footprint index (HFI), the intensity of human activities on the plateau was quantified. Additionally, an econometric model was constructed to analyze the impacts of the natural factors, the HFI, and policy factors on the sand fixation capacity. The results revealed that the average sand fixation quantity was 1368.0 t/km2/a, with a standard deviation of 1725.4 t/km2/a, and the highest value during the study period occurred in 2003. The average value of the HFI for 2020 was 6.69 with a standard deviation of 6.61, and the HFI exhibited a continuous growth trend from 2000 to 2020. Despite this growth, the average human activity intensity remained at a low level, with over 50 % of the area having an index value of <4.84. Overall, a strong negative correlation was observed between the sand fixation ecological capacity and the HFI on the QTP. However, extensive regions exhibited high values or low values for both indicators. The sand fixation capacity on the QTP is influenced by both natural and human factors. In light of these findings, suggestions are made for optimizing protected area design, rational control of human activity scales, and targeted human activity aggregation within certain regions as part of ecological conservation strategies. This study has implications for assessing sand fixation ecological functions in high-altitude regions and enhancing sand fixation capacity within the region, providing valuable practical guidance.

hsa_circ_0003596, as a novel oncogene, regulates the malignant behavior of renal cell carcinoma by modulating glycolysis.

BACKGROUND: This research was planned to analyze hsa_circ_0003596 (circCOL5A1) and glycolysis-focused mechanisms in renal cell carcinoma (RCC). METHODS: circCOL5A1, miR-370-5p, and PRKCSH levels were determined in RCC tissues and selected cell lines by RT-qPCR and/or Western blot. RCC cells after corresponding transfection were tested by colony formation assay, EdU assay, Transwell assay, and flow cytometry to analyze cell proliferation, invasion, migration, and apoptosis. Meanwhile, glycolysis in cells was evaluated by measuring glucose consumption, lactic acid, and ATP production, as well as immunoblotting for HK2 and PKM2. In addition, circCOL5A1 knockdown was performed in animal experiments to observe tumor growth and glycolysis. Finally, the ceRNA network between circCOL5A1, miR-370-5p, and PRKCSH was studied by luciferase reporter assay and RIP experiment. RESULTS: circCOL5A1 and PRKCSH were highly expressed and miR-370-5p was poorly expressed in RCC. circCOL5A1 knockdown depressed RCC proliferation, invasion, migration, and glycolysis, and enhanced apoptosis. circCOL5A1 competitively adsorbed miR-370-5p. Artificial upregulation of miR-370-5p saved the pro-tumor effect of circCOL5A1 on RCC cells, as evidenced by suppression of tumor malignancy and glycolysis. miR-370-5p targeted PRKCSH. PRKCSH overexpression contributed to a reversal of the anti-tumor effect of circCOL5A1 silencing. Silencing circCOL5A1 inhibited RCC tumor growth and glycolysis. CONCLUSIONS: circCOL5A1 regulates the malignant behavior of RCC by modulating glycolysis.

[Anesthetic management of Stanford type A aortic dissection operation].

OBJECTIVE: To explore the anesthetic management experiences of patients with Stanford A aortic dissection undergoing surgical treatment through moderate or deep hypothermia circulatory arrest (DHCA). METHODS: From June 2008 to December 2011, a total of 77 patients undergoing surgical treatment of Stanford A aortic dissection was recruited. RESULTS: Cardiopulmonary bypass (CPB) was established under general anesthesia in all patients. The procedures included moderate hypothermia (n = 51) and DHCA (n = 26). The total surgical duration was 152 - 600 (292 ± 91) min, CPB time 38 - 310 (128 ± 43) min and aortic cross-clamp time 31 - 169 (87 ± 26) min. The time of circulatory arrest under deep hypothermia was 20 - 113 (41 ± 19) min in 26 patients. Among 77 patients, there were 5 intraoperative and 7 postoperative fatalities. The remained 65 patients were discharged postoperatively and received a regular outpatient follow-up. None of them died or required reoperation. CONCLUSION: Surgical treatment is appropriate and efficient for the patients with Stanford A aortic dissection. During surgery, the keys of preventing neurological complications are blood volume monitoring and blood protection.

Non-Linear Association between Folate/Vitamin B12 Status and Cognitive Function in Older Adults.

Although folate and vitamin B12 status have long been implicated in cognitive function, there is no consensus on the threshold of folate and vitamin B12 for assessing their impacts on cognition. The goal of this study was to detail the association between folate and vitamin B12 with cognitive performance. We analyzed cross-sectional data of older adults (≥60 y; n = 2204) from the NHANES (National Health and Nutrition Examination Surveys) cohort from 2011-2014. The restricted cubic spline model was used for describing the associations between serum total folate, RBC folate, 5-methyltetrahydrofolate, and vitamin B12 and the Consortium to Establish a Registry for Alzheimer's Disease Word Learning (CERAD-WL) and Delayed Recall (CERAD-DR) tests, the Animal Fluency (AF) test, and the Digit Symbol Substitution Test (DSST), respectively. Older adults with a different folate and vitamin B12 status were clustered by artificial intelligence unsupervised learning. The statistically significant non-linear relationships between the markers of folate or vitamin B12 status and cognitive function were found after adjustments for potential confounders. Inverse U-shaped associations between folate/vitamin B12 status and cognitive function were observed, and the estimated breakpoint was described. No statistically significant interaction between vitamin B12 and folate status on cognitive function was observed in the current models. In addition, based on the biochemical examination of these four markers, older adults could be assigned into three clusters representing relatively low, medium, and high folate/vitamin B12 status with significantly different scores on the CERAD-DR and DSST. Low or high folate and vitamin B12 status affected selective domains of cognition, and was associated with suboptimal cognitive test outcomes.

Emerging Roles of Microglia in Neuro-vascular Unit: Implications of Microglia-Neurons Interactions.

Microglia, which serve as the defensive interface of the nervous system, are activated in many neurological diseases. Their role as immune responding cells has been extensively studied in the past few years. Recent studies have demonstrated that neuronal feedback can be shaped by the molecular signals received and sent by microglia. Altered neuronal activity or synaptic plasticity leads to the release of various communication messages from neurons, which in turn exert effects on microglia. Research on microglia-neuron communication has thus expanded from focusing only on neurons to the neurovascular unit (NVU). This approach can be used to explore the potential mechanism of neurovascular coupling across sophisticated receptor systems and signaling cascades in health and disease. However, it remains unclear how microglia-neuron communication happens in the brain. Here, we discuss the functional contribution of microglia to synapses, neuroimmune communication, and neuronal activity. Moreover, the current state of knowledge of bidirectional control mechanisms regarding interactions between neurons and microglia are reviewed, with a focus on purinergic regulatory systems including ATP-P2RY12R signaling, ATP-adenosine-A1Rs/A2ARs, and the ATP-pannexin 1 hemichannel. This review aims to organize recent studies to highlight the multifunctional roles of microglia within the neural communication network in health and disease.

The hidden costs of desert development.

Economic benefits and ecological restoration are the leading drivers of desert development through man-made oasis expansion. However, the sustainability of oasis expansion in combating desertification while promoting economic growth remains unclear, though such knowledge is critical for future desert development across the globe. To address this knowledge gap, a comprehensive assessment integrating meteorological, groundwater and remote-sensing data as well as groundwater simulation datasets was conducted to evaluate the spatial-temporal changes in the desert-oasis ecotone of northwest China over the past six decades. Desert development causes a rapid decline in the surrounding groundwater table, increases pollution in soil and groundwater and is associated with an increased frequency of strong sandstorms. Desert development seems to have improved the environment and promoted the economy, but there is a huge cost for the overexploitation of water resources and the transfer of pollution from surface to underground, which could cause deserts to degrade further.

The successful treatment of systemic toxic induced paraquat poisoning by skin absorption: case reports and a literature review.

Paraquat (PQ) poisoning is life-threatening, can cause acute organ damage, and has a high mortality. However, cases of skin absorption induced by PQ poisoning are rare. This report describes a case where PQ was absorbed by the patient's skin, causing severe organ damage. Having accidentally touched PQ on his skin, the patient, whose skin festered, became damaged, red, and swollen, developed serious systemic toxic symptoms. The patient recovered after systemic treatment. Generally speaking, being poisoned by PQ through skin absorption is rare. By analyzing the reported PQ poisoning through skin absorption and by reviewing the relevant literature, this paper aims to explore successful treatments for PQ poisoning through skin absorption and to provide treatment guidance for physicians encountering such cases.

KIR and HLA gene combinations in Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada (VKH) disease is a putative autoimmune ocular inflammatory disease and is known to be associated with HLA-DR4 and -DR1 in Mestizos. We examined the genes encoding KIR receptors and human leukocyte antigen (HLA) class I ligands in patients with VKH disease and compared to published controls. We found trends toward more group B KIR haplogroups (p=0.059), with more activating KIR genes, in patients compared to controls. All putative activating KIR-HLA combinations were more common in patients, and some inhibitory KIR-HLA combinations were more common in controls, although the differences were not statistically significant. The trends observed in this study are consistent with those reported for other autoimmune diseases.

Graphene oxide regulates endoplasmic reticulum stress: autophagic pathways in nasopharyngeal carcinoma cells.

During carcinogenesis, growth, proliferation, invasion and metastasis, increasing evidence shows that autophagy and endoplasmic reticulum stress (ER stress) are regulated in nasopharyngeal carcinoma, a finding drawing more attention from physicians and scientists. As one of the carbon-based nano-materials, graphene oxide (GO) has been extensively used for its advantages, such as biocompatibility, an ultrahigh surface to volume ratio, abundant surface groups, and a special photothermal effect. The present study is designed to explore the effects of GO on autophagy and ER stress in nasopharyngeal carcinoma cells. Our findings will provide scientific bases for the clinical application of GO and the development of new analogues. GO inhibits the proliferation of HONE1 cells, promotes their apoptosis in a concentration-dependent manner and enhances the expression of the ER stress chaperone GRP78 in HONE1 cells. These results suggest that GO could affect HONE1 cells through the autophagic and ER stress pathways. Thus, GO inhibits the proliferation of nasopharyngeal carcinoma cells via the induction of cytotoxic autophagy. In addition, ER stress is also activated as an adaptive response, so blocking ER stress may enhance the sensitivity of nasopharyngeal carcinoma cells to GO.

Repeated cardiac arrest caused by an air embolism during hepatic resection: A case report.

RATIONALE: Although venous air embolism (VAE) during liver operation has been reported occasionally, fatal VAE in hepatic resection is uncommon. Prompt detection of VAE by transesophageal echocardiography (TEE) is crucial for effective therapy. We describe a case of fatal VAE that caused repeated cardiac arrest during hepatic resection and was confirmed by TEE. PATIENT CONCERNS: A 51-year-old woman with a body weight of 50 kg underwent partial liver resection due to intrahepatic duct calculus. She had a 1-year history of intrahepatic duct calculus without cardiopulmonary disease. The operation was performed under general anesthesia combined with epidural block. When the inferior vena cava was compressed, the PetCO2 level decreased abruptly from 30 to 10 mmHg, followed by a decrease in SpO2 and the development of hypotension. Her heart rate increased with ST interval elevation on electrocardiography monitoring. Ephedrine and phenylephrine were administered immediately but had little effect. Cardiac arrest occurred. DIAGNOSES: Air embolism was detected by TEE. INTERVENTIONS: Resuscitation was successful although cardiac arrest occurred repeatedly. OUTCOMES: The patient returned to consciousness 6 hours postoperatively but died of multiorgan dysfunction 10 days later. LESSONS: Fatal air embolism may happen during hepatic resection. Prompt detection of VAE by TEE is crucial for effective therapy and should always be available during hepatic resection.

Perioperative Single-Donor Platelet Apheresis and Red Blood Cell Transfusion Impact on 90-Day and Overall Survival in Living Donor Liver Transplantation.

BACKGROUND:: Although many previous studies have confirmed that perioperative blood transfusion is associated with poor outcomes after liver transplantation (LT), few studies described the influence of single-donor platelet apheresis transfusion in living donor LT (LDLT). This study aimed to assess the effect of blood products on outcomes for LDLT recipients, focusing on apheresis platelets. METHODS:: This retrospective study included 126 recipients who underwent their first adult-to-adult LDLT. Twenty-four variables including consumption of blood products of 126 LDLT recipients were assessed for their link to short-term outcomes and overall survival. Kaplan-Meier survival curve and the log-rank test were used for recipient survival analysis. A multivariate Cox proportional-hazard model and a propensity score analysis were applied to adjust confounders after potential risk factors were identified by a univariate Cox analysis. RESULTS: Patients who received apheresis platelet transfusion had a lower 90-day cumulative survival (78.9% vs. 94.2%, P = 0.009), but had no significant difference in overall survival in the Cox model, compared with those without apheresis platelet transfusion. Units of apheresis platelet transfusion (hazard ratio [HR] = 3.103, 95% confidence interval [CI]: 1.720-5.600, P < 0.001) and preoperative platelet count (HR = 0.170, 95% CI: 0.040-0.730, P = 0.017) impacted 90-day survival independently. Multivariate Cox regression analysis also found that units of red blood cell (RBC) transfusion (HR = 1.036, 95% CI: 1.006-1.067, P = 0.018), recipient's age (HR = 1.045, 95% CI: 1.005-1.086, P = 0.025), and ABO blood group comparison (HR = 2.990, 95% CI: 1.341-6.669, P = 0.007) were independent risk factors for overall survival after LDLT. CONCLUSIONS:: This study suggested that apheresis platelets were only associated with early mortality but had no impact on overall survival in LDLT. Units of RBC, recipient's age, and ABO group comparison were independent predictors of long-term outcomes.

Hyperosmolarity-induced apoptosis in human corneal epithelial cells is mediated by cytochrome c and MAPK pathways.

PURPOSE: To study whether hyperosmolarity induces apoptosis in human corneal epithelial cells through cytochrome c-mediated death pathways and by activation of mitogen-activated protein kinases (MAPKs). METHODS: Primary human corneal epithelial cells cultured in normal osmolar media (312 mOsM) were switched to hyperosmolar media (450, 500, and 550 mOsM) by adding 70, 90, and 120 mM NaCl, respectively, with or without the c-jun N-terminal kinase (JNK) inhibitor SB202190 or the extracellular-regulated kinase (ERK) inhibitor PD98059. Apoptosis was assessed by the ApopTag In Situ Oligo Ligation (ISOL) assay. Confocal microscopy was used to detect cytochrome c and active caspase-3. Total RNA was extracted and subjected to reverse transcriptase-polymerase chain reaction for apoptosis-associated genes. Western blots were performed on cell extracts for the apoptogenic molecules cytochrome c and Smac/DIABLO, and phospho-JNK and ERK. RESULTS: ISOL-positive apoptotic cells significantly increased from 3.3 +/- 1.6% in control medium to 11.4 +/- 5.8%, 18.9 +/- 4.8%, and 43.9 +/- 8.8% in 70, 90, and 120 mM NaCl added media, respectively. The 90 mM NaCl high saline medium notably increased release of cytochrome c and Smac/DIABLO from mitochondria; activated caspase-3, JNK and ERK; stimulated mRNA expression of interleukin-1-converting enzyme and Bax; and reduced Bcl2 expression. SB202190 and PD98059 significantly suppressed hyperosmolarity-induced JNK/ERK activation and ISOL-positive cells. In addition, PD98059 inhibited the release of cytochrome c and Smac/DIABLO from mitochondria. CONCLUSIONS: These findings show that hyperosmolarity induces apoptosis of human corneal epithelial cells through a cytochrome c-mediated death pathway, which may be mediated by JNK and ERK MAPK signaling pathways.

[Risk factors of pinhole infection in the fractured lower limbs after external fixation: a case-control study].

OBJECTIVE: To investigate the risk factors of pinhole infection in the fractured lower limbs after external fixation. METHODS: The case-control study was designed. From May 2009 to May 2014, the clinical data of 272 patients with lower limb fracture treated by external fixation device were collected. All the patients were divided into two groups according to post-operative pinhole infection. There were 29 cases in the case group including 23 males and 6 females. The age of patients in case group ranged from 25 to 77 years old,with the average age of (53.41 ± 12.77) years old. There were 243 cases in control group including 217 males and 26 females. The age of patients in the control group ranged from 27 to 78 years old, with the average age of (48.71 ± 11.87) years old. There were nine risk factors observed in our study including age, gender, fixed time by external fixation device, diabetes, time in bed, smoking, operation condition of other parts in the body, infection condition of other parts in the body. RESULTS: The results of univariate analysis showed that there were statistically significant differences among age (χ² = 15.708, P < 0.001), fixed time by external fixation device (χ² = 11.940, P < 0.001), severity of the lower limb fracture (χ² =15.438, P < 0.001), diabetes (χ² = 8.519, P = 0.004) and time in bed (χ² = 7.165, P = 0.007) between case group and control group. The results of Logistic regression analysis showed that the risk factors of pinhole infection after fixed by external fixation device in the lower limb fracture were the advanced age (OR = 8.327, P < 0.001), fixed time by external fixation device (OR = 6.795, P < 0.001), diabetes (OR = 4.965, P = 0.001) and time in bed (OR = 4.864, P = 0.008). CONCLUSION: The advanced age, long fixed time, diabetes and long time in bed could increase the risk of pinhole infection after external fixation in the lower limbs with fracture.

Doxycycline inhibits TGF-beta1-induced MMP-9 via Smad and MAPK pathways in human corneal epithelial cells.

PURPOSE: To evaluate the effects of TGF-beta1 and doxycycline on production of gelatinase MMP-9 and activation of Smad, c-Jun N-terminal kinase (JNK), extracellular-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways in human corneal epithelial cells. METHODS: Primary human corneal epithelial cells were cultured to confluence. The cells were treated with different concentrations of TGF-beta1 (0.1, 1, or 10 ng/mL), with or without TGF-beta1-neutralizing mAb (5 microg/mL), SP600125 (30 microM), PD98059 (40 microM), SB202190 (20 microM), or doxycycline (5-40 microg/mL) for different lengths of time. Conditioned media were collected from cultures treated for 24 to 48 hours to evaluate the MMP-9 production by zymography and activity assay. Total RNA was isolated from cells treated for 6 to 24 hours to evaluate MMP-9 expression by semiquantitative RT-PCR and Northern hybridization. Cells treated for 5 to 60 minutes were lysed in RIPA buffer for Western blot with phospho-specific antibodies against Smad2, JNK1/2, ERK1/2, or p38. RESULTS: TGF-beta1 increased expression, production, and activity of MMP-9 by human corneal epithelial cells in a concentration-dependent fashion. TGF-beta1 also induced activation of Smad2, JNK1/2, ERK1/2, and p38 within 5 to 15 minutes, with peak activation at 15 to 60 minutes. Doxycycline markedly inhibited the TGF-beta1-induced production of MMP-9 and activation of the Smad, JNK1/2, ERK1/2, and p38 signaling pathways. Its inhibitory effects were of a magnitude similar to SP600125, PD98059, and SB202190, specific inhibitors of the JNK1/2, ERK1/2, and p38 pathways, respectively. CONCLUSIONS: These findings demonstrated that doxycycline inhibits TGF-beta1-induced MMP-9 production and activity, perhaps through the Smad and MAPK signaling pathways. These inhibitory effects may explain the reported efficacy of doxycycline in treating MMP-9-mediated ocular surface diseases.

Plasminogen kringle 5 inhibits alkali-burn-induced corneal neovascularization.

PURPOSE: Plasminogen kringle 5 (K5) is a potent angiogenic inhibitor. The purpose of the present study was to evaluate the therapeutic effect of K5 on alkali-burn-induced corneal neovascularization (NV) and to investigate its mechanism of action. METHODS: Corneal NV was induced in rabbits by NaOH. The rabbits received eye drops containing K5 or vehicle alone, four times per day. Corneal NV and inflammation were monitored every other day with a slit lamp microscope, and the length of the vessels in the cornea and the area of NV were measured. Vascular endothelial growth factor (VEGF) was determined by immunohistochemical and Western blot analyses. The TUNEL assay was used to assess the apoptosis of endothelial cells. The effects of K5 on primary bovine aortic endothelial cells (BAECs) were determined by MTT assay, flow cytometry, transmission electron microscopy, and DNA fragmentation assay. RESULTS: Alkali-burn-induced progressive corneal NV and inflammation in the cornea. K5 delayed the onset of corneal NV (P < 0.05) and decreased NV areas (P < 0.05) in a dose-dependent manner. K5 treatment, after the formation of corneal NV, induced regression of newly formatted vessels in the cornea. K5 decreased the inflammatory index in the corneas at different time points after the alkali burn. Corneal VEGF levels were reduced by K5 treatment. K5 inhibits proliferation and induces apoptosis in BAECs. CONCLUSIONS: Topical application of K5 may have therapeutic potential for the chemical burn-induced corneal NV and inflammation. The inhibitory effect of K5 on corneal NV may be by downregulation of VEGF expression.

Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy.

PURPOSE: To define the alterations of corneal nerves in aqueous tear deficiency dry eye patients with or without Sjögren syndrome and to identify the relationship between the morphologic changes of corneal nerves and the extent of dry eye. METHODS: Confocal microscopy was used to examine 38 consecutive aqueous tear deficiency patients (8 Sjögren syndrome and 30 non-Sjögren syndrome) and 30 age- and gender-matched normal controls. Images taken by Confocal2 slit-scanning microscope at subbasal epithelial cell layer of central cornea were analyzed. The number and density of corneal nerves and their size, beads, tortuosity, and branching pattern were compared. These data were correlated with age and the degree of dry eye. RESULTS: Sjögren syndrome patients showed a significant increase in average nerve number and tortuosity as compared with normal controls (P = 0.031 and 0.021, respectively). Severe nerve tortuosity (grade 4) and nerve branching appeared more frequently in aqueous tear deficiency than in normal subjects (P = 0.024 and 0.042, respectively). A decreased nerve number was observed with age in the normal controls (P = 0.002). However, such a correlation did not exist in aqueous tear deficiency. In aqueous tear deficiency, rose bengal staining score correlated positively with nerve density (P = 0.048) and nerve number (P = 0.001). Corneal fluorescein staining score was also positively correlated with nerve number (P = 0.027). CONCLUSIONS: Abnormal morphologic changes are observed in aqueous tear deficiency that are more severe in Sjögren syndrome. The distinct changes of corneal nerves include increased nerve number, tortuosity, and chances of branching, suggesting an attempted nerve regeneration. A strong correlation exists between the changes of nerve morphology and the degree of dry eye. These results provide some possible evidence for the abnormal corneal sensation in dry eye.

Stress-activated protein kinase signaling pathways in dry eye and ocular surface disease.

Inflammation is recognized as a key component in the pathogenesis of dry eye and a variety of ocular surface diseases. Stress-activated protein kinases have been identified as pathways signaling ocular surface stresses, such as increased tear film osmolarity and ultraviolet light exposure. Activation of these stress pathways results in transcription of stress related genes, including inflammatory cytokines (e.g. interleukin-1 and tumor necrosis factor (TNF)-alpha and matrix metalloproteinases (MMPs), such as MMP-9. Treatment of osmo-stressed cultured corneal epithelia with inhibitors of the stress associated kinase c-jun N-terminal kinases was found to decrease production of MMPs by these cells. These findings suggest that SAPKs may be key therapeutic targets for dry eye and ocular surface diseases.