Limbic Connectivity Underlies Pain Treatment Response in Small-Fiber Neuropathy.

OBJECTIVE: Small-fiber neuropathy (SFN) is characterized by neuropathic pain due to degeneration of small-diameter nerves in the skin. Given that brain reorganization occurs following chronic neuropathic pain, this study investigated the structural and functional basis of pain-related brain changes after skin nerve degeneration. METHODS: Diffusion-weighted and resting-state functional MRI data were acquired from 53 pathologically confirmed SFN patients, and the structural and functional connectivity of the pain-related network was assessed using network-based statistic (NBS) analysis. RESULTS: Compared with age- and sex-matched controls, the SFN patients exhibited a robust and global reduction of functional connectivity, mainly across the limbic and somatosensory systems. Furthermore, lower functional connectivity was associated with skin nerve degeneration measured by reduced intraepidermal nerve fiber density and better therapeutic response to anti-neuralgia medications, particularly for the connectivity between the insula and the limbic areas including the anterior and middle cingulate cortices. Similar to the patterns of functional connectivity changes, the structural connectivity was robustly reduced among the limbic and somatosensory areas, and the cognition-integration areas including the inferior parietal lobule. There was shared reduction of structural and functional connectivity among the limbic, somatosensory, striatal, and cognition-integration systems: (1) between the middle cingulate cortex and inferior parietal lobule and (2) between the thalamus and putamen. These observations indicate the structural basis underlying altered functional connectivity in SFN. INTERPRETATION: Our findings provide imaging evidence linking structural and functional brain dysconnectivity to sensory deafferentation caused by peripheral nerve degeneration and therapeutic responses for neuropathic pain in SFN. ANN NEUROL 2023;93:655-667.

Genotyping Array Design and Data Quality Control in the Million Veteran Program.

The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other 'omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP's substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.

Temporal shifts of the microbiome associated with antibiotic treatment of purpuric drug eruptions related to epidermal growth factor receptor inhibitors.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are selective and effective treatments for cancers with relevant mutations. Purpuric drug eruptions are an uncommon but clinically significant dermatological side effect related to EGFR inhibitor use that are associated with positive bacterial cultures and responsive to antibiotic treatment. However, the longitudinal temporal shifts in the skin microbiome that occur before and after antibiotic treatment of purpuric drug eruptions remain largely unknown. OBJECTIVES: To characterize temporal changes in the skin and mucosal microbiomes before and after antibiotic treatment of EGFR inhibitor-related purpuric drug eruptions. METHODS: Twelve patients who experienced EGFR inhibitor-related purpuric drug eruptions were recruited from a dermato-oncology clinic in Taiwan from May 2017 to April 2018. Swabs were obtained from skin lesions and the nasal mucosa before and after antibiotic treatment of purpuric drug eruptions. After the amplification and sequencing of bacterial 16S rRNA genes, the diversity and compositions of microbiomes sampled at different time points were compared. RESULTS: The alpha diversity (represented by the Shannon index) of the skin microbiome increased significantly in the recovered phase of purpuric drug eruptions compared with that of the active phase. By contrast, the nasal microbiome showed no significant change in alpha diversity. The relative abundance of Staphylococcus significantly decreased in samples from skin of the recovered phase, which was confirmed by analysis of compositions of microbiomes (ANCOM) and the ALDEx2 analysis packages in R. CONCLUSIONS: The cutaneous microbiome of purpuric drug eruptions showed a significant increase in alpha diversity and a decrease in the relative abundance of Staphylococcus following antibiotic treatment. These findings may help guide antimicrobial therapy of this EGFR inhibitor-related condition.

dBRWD3 Regulates Tissue Overgrowth and Ectopic Gene Expression Caused by Polycomb Group Mutations.

To maintain a particular cell fate, a unique set of genes should be expressed while another set is repressed. One way to repress gene expression is through Polycomb group (PcG) proteins that compact chromatin into a silent configuration. In addition to cell fate maintenance, PcG proteins also maintain normal cell physiology, for example cell cycle. In the absence of PcG, ectopic activation of the PcG-repressed genes leads to developmental defects and malignant tumors. Little is known about the molecular nature of ectopic gene expression; especially what differentiates expression of a given gene in the orthotopic tissue (orthotopic expression) and the ectopic expression of the same gene due to PcG mutations. Here we present that ectopic gene expression in PcG mutant cells specifically requires dBRWD3, a negative regulator of HIRA/Yemanuclein (YEM)-mediated histone variant H3.3 deposition. dBRWD3 mutations suppress both the ectopic gene expression and aberrant tissue overgrowth in PcG mutants through a YEM-dependent mechanism. Our findings identified dBRWD3 as a critical regulator that is uniquely required for ectopic gene expression and aberrant tissue overgrowth caused by PcG mutations.

Review of flow rate estimates of the Deepwater Horizon oil spill.

The unprecedented nature of the Deepwater Horizon oil spill required the application of research methods to estimate the rate at which oil was escaping from the well in the deep sea, its disposition after it entered the ocean, and total reservoir depletion. Here, we review what advances were made in scientific understanding of quantification of flow rates during deep sea oil well blowouts. We assess the degree to which a consensus was reached on the flow rate of the well by comparing in situ observations of the leaking well with a time-dependent flow rate model derived from pressure readings taken after the Macondo well was shut in for the well integrity test. Model simulations also proved valuable for predicting the effect of partial deployment of the blowout preventer rams on flow rate. Taken together, the scientific analyses support flow rates in the range of ∼50,000-70,000 barrels/d, perhaps modestly decreasing over the duration of the oil spill, for a total release of ∼5.0 million barrels of oil, not accounting for BP's collection effort. By quantifying the amount of oil at different locations (wellhead, ocean surface, and atmosphere), we conclude that just over 2 million barrels of oil (after accounting for containment) and all of the released methane remained in the deep sea. By better understanding the fate of the hydrocarbons, the total discharge can be partitioned into separate components that pose threats to deep sea vs. coastal ecosystems, allowing responders in future events to scale their actions accordingly.

Scientific basis for safely shutting in the Macondo Well after the April 20, 2010 Deepwater Horizon blowout.

As part of the government response to the Deepwater Horizon blowout, a Well Integrity Team evaluated the geologic hazards of shutting in the Macondo Well at the seafloor and determined the conditions under which it could safely be undertaken. Of particular concern was the possibility that, under the anticipated high shut-in pressures, oil could leak out of the well casing below the seafloor. Such a leak could lead to new geologic pathways for hydrocarbon release to the Gulf of Mexico. Evaluating this hazard required analyses of 2D and 3D seismic surveys, seafloor bathymetry, sediment properties, geophysical well logs, and drilling data to assess the geological, hydrological, and geomechanical conditions around the Macondo Well. After the well was successfully capped and shut in on July 15, 2010, a variety of monitoring activities were used to assess subsurface well integrity. These activities included acquisition of wellhead pressure data, marine multichannel seismic profiles, seafloor and water-column sonar surveys, and wellhead visual/acoustic monitoring. These data showed that the Macondo Well was not leaking after shut in, and therefore, it could remain safely shut until reservoir pressures were suppressed (killed) with heavy drilling mud and the well was sealed with cement.

Post Audit of Simulated Groundwater Flow to a Short-Lived (2019 to 2020) Crater Lake at Kilauea Volcano.

About 14.5 months after the 2018 eruption and summit collapse of Kilauea Volcano, Hawai'i, liquid water started accumulating in the deepened summit crater, forming a lake that attained 51 m depth before rapidly boiling off on December 20, 2020, when an eruption from the crater wall poured lava into the lake. Modeling the growth of the crater lake at Kilauea summit is important for assessing the potential for explosive volcanism. Our current understanding of the past 2500 years of eruptive activity at Kilauea suggests a slight dominance of explosive behavior over effusive. The deepened summit crater and presence of the crater lake in 2019 raised renewed concerns about explosive activity. Groundwater models using hydraulic-property data from a nearby drillhole successfully forecast the timing and rate of lake filling. Here we compare the groundwater-model predictions with observational data through the demise of the crater lake, examine the implications for local water-table configuration, consider the potential role of evaporation and recharge (neglected in previous models), and briefly discuss the energetics of the rapid boil-off. This post audit of groundwater-flow models of Kilauea summit shows that simple models can sometimes be used effectively to simulate complex settings such as volcanoes.

Impaired brain network architecture as neuroimaging evidence of pain in diabetic neuropathy.

AIMS: To investigate alterations in structural brain networks due to chronic diabetic neuropathic pain. METHODS: The current study recruited 24 patients with painful diabetic neuropathy (PDN) to investigate the influences of chronic pain on the brain. Thirteen patients with painless diabetic neuropathy (PLDN) and 24 healthy adults were recruited as disease and healthy controls. White matter connectivity of the brain networks constructed by diffusion tractography was compared across groups using the Network-based statistic (NBS) method. Graph theoretical analysis was further applied to assess topological changes of the brain networks. RESULTS: The PDN patients had a significant reduction in white matter connectivity compared with PLDN and controls in the limbic and temporal regions, particularly the insula, hippocampus and parahippocampus, the amygdala, and the middle temporal gyrus. The PDN patients also exhibited an altered topology of the brain networks with reduced global efficiency and betweenness centrality. CONCLUSION: The current findings indicate that topological alterations of brain networks may serve as a biomarker for pain-induced maladaptive reorganization of the brain in PDN. Given the high prevalence of diabetes worldwide, novel insights from network sciences to investigate the central mechanisms of diabetic neuropathic pain are warranted.

Brain Mechanisms of Pain and Dysautonomia in Diabetic Neuropathy: Connectivity Changes in Thalamus and Hypothalamus.

CONTEXT: About one-third of diabetic patients suffer from neuropathic pain, which is poorly responsive to analgesic therapy and associated with greater autonomic dysfunction. Previous research on diabetic neuropathy mainly links pain and autonomic dysfunction to peripheral nerve degeneration resulting from systemic metabolic disturbances, but maladaptive plasticity in the central pain and autonomic systems following peripheral nerve injury has been relatively ignored. OBJECTIVE: This study aimed to investigate how the brain is affected in painful diabetic neuropathy (PDN), in terms of altered structural connectivity (SC) of the thalamus and hypothalamus that are key regions modulating nociceptive and autonomic responses. METHODS: We recruited 25 PDN and 13 painless (PLDN) diabetic neuropathy patients, and 27 healthy adults as controls. The SC of the thalamus and hypothalamus with limbic regions mediating nociceptive and autonomic responses was assessed using diffusion tractography. RESULTS: The PDN patients had significantly lower thalamic and hypothalamic SC of the right amygdala compared with the PLDN and control groups. In addition, lower thalamic SC of the insula was associated with more severe peripheral nerve degeneration, and lower hypothalamic SC of the anterior cingulate cortex was associated with greater autonomic dysfunction manifested by decreased heart rate variability. CONCLUSION: Our findings indicate that alterations in brain structural connectivity could be a form of maladaptive plasticity after peripheral nerve injury, and also demonstrate a pathophysiological association between disconnection of the limbic circuitry and pain and autonomic dysfunction in diabetes.

The Feasibility of Tai Chi Exercise as a Beneficial Mind-Body Intervention in a Group of Community-Dwelling Stroke Survivors with Symptoms of Depression.

Depression is prevalent among one-third to two-thirds of acute and chronic stroke survivors. Despite the availability of pharmacotherapies and/or psychotherapies, depression persists, even for 5-10 years after stroke, reflecting limited treatment responses and/or adherence to this conventional care. Mind-body interventions are commonly used among adults to ameliorate depressive symptoms. Thus, the feasibility of Tai Chi, alongside conventional care, to manage poststroke depression was investigated using a single-group pre-post intervention design. Recruitment and retention, intervention adherence, safety, acceptability, and fidelity were assessed. Symptoms of depression, anxiety, and stress were assessed using standardized questionnaires, objective sleep was assessed via a research-grade triaxial accelerometer, and blood samples were taken to measure oxidative stress, inflammatory markers, and a neurotrophic growth factor using commercially available kits per manufacturer's protocol. Pre-post intervention changes were assessed using paired t-tests. We enrolled stroke survivors (N = 11, mean age = 69.7 ± 9.3) reporting depression symptoms. After the intervention, we observed significant reductions in symptoms of depression (-5.3 ± 5.9, p=0.01), anxiety (-2.2 ± 2.4, p=0.01), and stress (-4.6 ± 4.8, p=0.01), along with better sleep efficiency (+1.8 ± 1.8, p=0.01), less wakefulness after sleep onset (-9.3 ± 11.6, p=0.04), and less time awake (-9.3 ± 11.6, p=0.04). There was a 36% decrease in oxidative stress (p=0.02), though no significant changes in the other biomarkers were found (all p values >0.05). Tai Chi exercise is a feasible intervention that can be used alongside conventional care to manage poststroke depression, aid in reducing symptoms of anxiety and stress, and improve sleep.

Brain imaging signature of neuropathic pain phenotypes in small-fiber neuropathy: altered thalamic connectome and its associations with skin nerve degeneration.

ABSTRACT: Small-fiber neuropathy (SFN) has been traditionally considered as a pure disorder of the peripheral nervous system, characterized by neuropathic pain and degeneration of small-diameter nerve fibers in the skin. Previous functional magnetic resonance imaging studies revealed abnormal activations of pain networks, but the structural basis underlying such maladaptive functional alterations remains elusive. We applied diffusion tensor imaging to explore the influences of SFN on brain microstructures. Forty-one patients with pathology-proven SFN with reduced skin innervation were recruited. White matter connectivity with the thalamus as the seed was assessed using probabilistic tractography of diffusion tensor imaging. Patients with SFN had reduced thalamic connectivity with the insular cortex and the sensorimotor areas, including the postcentral and precentral gyri. Furthermore, the degree of skin nerve degeneration, measured by intraepidermal nerve fiber density, was associated with the reduction of connectivity between the thalamus and pain-related areas according to different neuropathic pain phenotypes, specifically, the frontal, cingulate, motor, and limbic areas for burning, electrical shocks, tingling, mechanical allodynia, and numbness. Despite altered white matter connectivity, there was no change in white matter integrity assessed with fractional anisotropy. Our findings indicate that alterations in structural connectivity may serve as a biomarker of maladaptive brain plasticity that contributes to neuropathic pain after peripheral nerve degeneration.

Selenium supplementation and insulin resistance in a randomized, clinical trial.

Objective: While controversial, observational and randomized clinical trial data implicate the micronutrient selenium (Se) in the development of type 2 diabetes (T2D). The aim of this study was to test the hypothesis that Se supplementation adversely affects pancreatic ß-cell function and insulin sensitivity. Research design and methods: In a subset of 400 individuals participating in a randomized, placebo-controlled trial of Se at 200 µg/day for colorectal adenomatous polyps, fasting plasma glucose and insulin were measured before randomization and within 6 months of completing intervention. Change in the homeostasis model assessment-ß cell function (HOMA2-%ß) and insulin sensitivity (HOMA2-%S) were compared between arms. A subgroup of 175 (79 Se and 96 placebo) participants underwent a modified oral glucose tolerance test (mOGTT) at the end of intervention and change in glucose values was assessed. Results: No statistically significant differences were observed for changes in HOMA2-%ß or HOMA2-%S between those who received Se compared with placebo. After a mean of 2.9 years on study, mean HOMA2-%ß values were 3.1±24.0 and 3.1±29.8 for the Se and placebo groups, respectively (p=0.99). For HOMA2-%S, the values were -0.5±223.2 and 80.9±1530.9 for the Se and placebo groups, respectively (p=1.00). Stratification by sex or age did not reveal any statistically significant effects on insulin sensitivity by treatment group. For mOGTT, mean baseline fasting blood glucose concentrations were significantly higher among participants in the placebo group compared with the Se group (96.6±14.6 and 92.3±12.0, respectively; p=0.04), a trend which remained through the 20 min assessment. Conclusions: These findings do not support a significant adverse effect of daily Se supplementation with 200 µg/day of selenized yeast on ß-cell function or insulin sensitivity as an explanation for previously reported associations between Se and T2D. Further clarification of longer term effects of Se is needed. Clinical trial registry: NIH Clinical Trials.gov number NCT00078897.

Bioremediation in Fractured Rock: 2. Mobilization of Chloroethene Compounds from the Rock Matrix.

A mass balance is formulated to evaluate the mobilization of chlorinated ethene compounds (CE) from the rock matrix of a fractured mudstone aquifer under pre- and postbioremediation conditions. The analysis relies on a sparse number of monitoring locations and is constrained by a detailed description of the groundwater flow regime. Groundwater flow modeling developed under the site characterization identified groundwater fluxes to formulate the CE mass balance in the rock volume exposed to the injected remediation amendments. Differences in the CE fluxes into and out of the rock volume identify the total CE mobilized from diffusion, desorption, and nonaqueous phase liquid dissolution under pre- and postinjection conditions. The initial CE mass in the rock matrix prior to remediation is estimated using analyses of CE in rock core. The CE mass mobilized per year under preinjection conditions is small relative to the total CE mass in the rock, indicating that current pump-and-treat and natural attenuation conditions are likely to require hundreds of years to achieve groundwater concentrations that meet regulatory guidelines. The postinjection CE mobilization rate increased by approximately an order of magnitude over the 5 years of monitoring after the amendment injection. This rate is likely to decrease and additional remediation applications over several decades would still be needed to reduce CE mass in the rock matrix to levels where groundwater concentrations in fractures achieve regulatory standards.

Bioremediation in Fractured Rock: 1. Modeling to Inform Design, Monitoring, and Expectations.

Field characterization of a trichloroethene (TCE) source area in fractured mudstones produced a detailed understanding of the geology, contaminant distribution in fractures and the rock matrix, and hydraulic and transport properties. Groundwater flow and chemical transport modeling that synthesized the field characterization information proved critical for designing bioremediation of the source area. The planned bioremediation involved injecting emulsified vegetable oil and bacteria to enhance the naturally occurring biodegradation of TCE. The flow and transport modeling showed that injection will spread amendments widely over a zone of lower-permeability fractures, with long residence times expected because of small velocities after injection and sorption of emulsified vegetable oil onto solids. Amendments transported out of this zone will be diluted by groundwater flux from other areas, limiting bioremediation effectiveness downgradient. At nearby pumping wells, further dilution is expected to make bioremediation effects undetectable in the pumped water. The results emphasize that in fracture-dominated flow regimes, the extent of injected amendments cannot be conceptualized using simple homogeneous models of groundwater flow commonly adopted to design injections in unconsolidated porous media (e.g., radial diverging or dipole flow regimes). Instead, it is important to synthesize site characterization information using a groundwater flow model that includes discrete features representing high- and low-permeability fractures. This type of model accounts for the highly heterogeneous hydraulic conductivity and groundwater fluxes in fractured-rock aquifers, and facilitates designing injection strategies that target specific volumes of the aquifer and maximize the distribution of amendments over these volumes.

Biomarkers of neuropathic pain in skin nerve degeneration neuropathy: contact heat-evoked potentials as a physiological signature.

Contact heat-evoked potentials (CHEPs) have become an established method of assessing small-fiber sensory nerves; however, their potential as a physiological signature of neuropathic pain symptoms has not been fully explored. To investigate the diagnostic efficacy in examining small-fiber sensory nerve degeneration, the relationship with skin innervations, and clinical correlates with sensory symptoms, we recruited 188 patients (115 men) with length-dependent sensory symptoms and reduced intraepidermal nerve fiber (IENF) density at the distal leg to perform CHEP, quantitative sensory testing, and nerve conduction study. Fifty-seven age- and sex-matched controls were enrolled for comparison of CHEP and skin innervation. Among patients with neuropathy, 144 patients had neuropathic pain and 64 cases had evoked pain. Compared with quantitative sensory testing and nerve conduction study parameters, CHEP amplitudes showed the highest sensitivity for diagnosing small-fiber sensory nerve degeneration and exhibited the strongest correlation with IENF density in multiple linear regression. Contact heat-evoked potential amplitudes were strongly correlated with the degree of skin innervation in both patients with neuropathy and controls, and the slope of the regression line between CHEP amplitude and IENF density was higher in patients with neuropathy than in controls. Patients with evoked pain had higher CHEP amplitude than those without evoked pain, independent of IENF density. Receiver operating characteristic analysis showed that CHEP had better performance in diagnosing small-fiber sensory nerve degeneration than thermal thresholds. Furthermore, CHEPs showed superior classification accuracy with respect to evoked pain. In conclusion, CHEP is a sensitive tool to evaluate pathophysiology of small-fiber sensory nerve and serves as a physiological signature of neuropathic pain symptoms.

Determining anisotropic transmissivity using a simplified Papadopulos method.

The straight-line method presented by Papadopulos requires a minimum of three observation wells for determining the transmissivity tensor of a homogeneous and anisotropic aquifer. A simplification of this method was developed for fractured aquifers where the principal directions of the transmissivity tensor are known prior to implementation, such as when fracture patterns on outcropping portions of the aquifer may be used to infer the principal directions. This new method assumes that observation wells are drilled along the two principal directions from the pumped well, thus reducing the required number of observation wells to two. This method was applied for an aquifer test in the fractured Navajo Sandstone of southwestern Utah and yielded minimum and maximum principal transmissivity values of 70 and 1800 m(2)/d, respectively, indicating an anisotropy ratio of approximately 24 to 1.

Pathophysiology of Small-Fiber Sensory System in Parkinson's Disease: Skin Innervation and Contact Heat Evoked Potential.

Sensory symptoms are frequent nonmotor complaints in patients with Parkinson's disease (PD). However, few investigations integrally explored the physiology and pathology of the thermonociceptive pathway in PD. We aim to investigate the involvement of the thermonociceptive pathway in PD.Twenty-eight PD patients (16 men, with a mean age and standard deviation of 65.6 ±â€Š10.7 years) free of neuropathic symptoms and systemic disorders were recruited for the study and compared to 23 age- and gender-matched control subjects (12 men, with a mean age and standard deviation of 65.1 ±â€Š9.9 years). We performed skin biopsy, contact heat-evoked potential (CHEP), and quantitative sensory tests (QST) to study the involvement of the thermonociceptive pathway in PD.The duration of PD was 7.1 ±â€Š3.2 (range 2-17 years) years and the UPDRS part III score was 25.6 ±â€Š9.7 (range 10-48) during the off period. Compared to control subjects, PD patients had reduced intra-epidermal nerve fiber (IENF) density (2.48 ±â€Š1.65 vs 6.36 ±â€Š3.19 fibers/mm, P < 0.001) and CHEP amplitude (18.02 ±â€Š10.23 vs 33.28 ±â€Š10.48 µV, P < 0.001). Twenty-three patients (82.1%) had abnormal IENF densities and 18 (64.3%) had abnormal CHEP. Nine patients (32.1%) had abnormal thermal thresholds in the feet. In total 27 patients (96.4%) had at least 1 abnormality in IENF, CHEP, or thermal thresholds of the foot, indicating dysfunctions in the small-fiber nerve system. In control subjects, CHEP amplitude linearly correlated with IENF density (P < 0.001). In contrast, this relationship disappeared in PD (P = 0.312) and CHEP amplitude was negatively correlated with motor severity of PD independent of age, gender, and anti-PD medication dose (P = 0.036), suggesting the influences of central components on thermonociceptive systems in addition to peripheral small-fiber nerves in PD.The present study suggested impairment of small-fiber sensory system at both peripheral and central levels is an intrinsic feature of PD, and skin biopsy, CHEP, and QST provided an integral approach for assessing such dysfunctions.

Imaging signatures of altered brain responses in small-fiber neuropathy: reduced functional connectivity of the limbic system after peripheral nerve degeneration.

Small-fiber neuropathy (SFN) is hallmarked by degeneration of small unmyelinated peripheral nerve fibers in the skin. Traditionally, it has been considered as a pure disorder of the peripheral nervous system. Nevertheless, previous work found that dysfunction of skin nerves led to abnormal recruitment of pain-related regions, suggesting that the brain may be affected in SFN. This report combined structural and functional magnetic resonance imaging to identify structural and functional changes in the brain of 19 patients with SFN compared with 17 healthy controls. We applied tensor-based morphometry to detect brain structural alterations in SFN. Greater volume reduction in pain-processing regions, particularly the bilateral anterior cingulate cortices (ACCs), was associated with greater depletion of intraepidermal nerve fibers, a pathological biomarker of skin nerve degeneration. Based on the hypothesis that structural alterations in the pain-processing regions might impair their functional connectivity, we further applied psychophysiological interaction analysis to assess functional connectivity of the ACCs during noxious heat stimulation. There was significant reduction in functional connectivity from the ACCs to the limbic areas (the parahippocampal gyrus and the posterior cingulate cortex), pain-processing area (the insula), and visuospatial areas (the cuneus). Moreover, the degree of reduction in functional connectivity for the ACC to the amygdala and the precuneus was linearly correlated with the severity of intraepidermal nerve fiber depletion. Our findings suggest that SFN is not a pure peripheral nervous system disorder. The pain-related brain networks tend to break into functionally independent components, with severity linked to the degree of skin nerve degeneration.

Photoinhibition of cyanobacteria and its application in cultural heritage conservation.

Light has bilateral effects on phototrophic organisms. As cyanobacteria in Roman hypogea are long acclimatized to dim environment, moderate intensity of illumination can be used to alleviate biodeterioration problems on the stone substrata. Moderate intensity of light inactivates cyanobacteria by causing photoinhibition, photobleaching and photodamage to the cells. The effectiveness of light depends not only on its intensity but also on the composition and pigmentation of the component cyanobacteria in the biofilms. Red light is the most effective for the species rich in phycocyanin and allophycocyanin, such as Leptolyngbya sp. and Scytonema julianum, whereas green light is effective to inhibit the species rich in phycoerythrin, like Oculatella subterranea. White light is effective to control the grayish and the black cyanobacteria, such as Symphyonemopsis sp. and Eucapsis sp. abundant in all of these pigments. Blue light is the least effective. 150 µmol photons m(-2)  s(-1) of blue light cannot cause biofilm damage while the same intensity of red, green or white irradiation for 14 days can severely damage the cyanobacterial cells in the biofilms due to ROS formation. Electron spin resonance spectroscopy detected the formation of radicals in different cyanobacterial cellular extracts exposed to 80 µmol photons m(-2)  s(-1) of light.

Effect of glycemic control on sudomotor denervation in type 2 diabetes.

OBJECTIVE: Sudomotor symptoms are a common component of diabetic autonomic neuropathy, but the pathology of sudomotor innervation and its relationship with glycemic control have remained obscured. RESEARCH DESIGN AND METHODS: We enrolled 42 patients (26 males and 16 females aged 56.64 ± 12.67 years) with diabetic neuropathy defined by symmetric distally predominant sensory symptoms, abnormal nerve conduction studies, and reduced intraepidermal nerve fiber density in the leg. Skin biopsies of the distal leg were immunostained with antiprotein gene product 9.5 for nerve fibers and counterstained with Congo red for sweat glands. Sweat gland innervation index (SGII) was quantified with a new computerized area-based morphometric system. RESULTS: Protein gene product 9.5(+) nerve terminals surrounded secretory coils of the sweat glands in the skin of control subjects. Sudomotor denervation was present in diabetic patients, manifesting as depletion of periglandular nerve fibers with lower SGII compared with 42 age- and sex-matched control subjects (2.54 ± 1.87 vs. 4.68 ± 1.51%, P < 0.001). The SGII was correlated with HbA(1c) (P = 0.011) and was lower in patients with anhidrosis of the feet compared with those with normal sweating of the feet (0.82 ± 0.69 vs. 3.00 ± 1.81%, P = 0.001). Sudomotor denervation was concordant with cardiac autonomic dysfunction as assessed with reduced heart rate variability (P = 0.003). CONCLUSIONS: Sudomotor denervation is a significant presentation of diabetic neuropathy, and the SGII was associated with HbA(1c). A skin biopsy offers a structural assessment of sudomotor innervation.