HLA-G expression in Merkel cell carcinoma and the correlation with Merkel cell polyomavirus infection.

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine cutaneous carcinoma with a high mortality rate. The MCC etiology is not fully understood. Merkel cell-associated polyomavirus (MCPyV) was found in MCC patients, indicating a risk factor for the tumor. Caucasian, elderly, and immunocompromised individuals are more likely to develop this tumor. HLA-G consists of a non-classical class I (Ib) HLA molecule with an immunoregulatory function and was associated with tumor escape in different types of tumors, nonetheless, never been studied in MCC. The purpose of this study was to evaluate the HLA-G expression and also to detect the MCPyV in MCC patients and correlate it with the clinical course of the disease. Forty-five MCC patients were included in a retrospective study. Formalin-fixed paraffin-embedded cutaneous skin biopsies were used by immunohistochemistry and RT-PCR to verify the HLA-G expression and MCPyV infection. HLA-G expression was found in 7 (15.6%), while the presence of MCPyV was detected in 28 (62.2%) of the studied patients. No significant association was found between HLA-G expression and MCPyV infection (p = 0.250). The presence of MCPyV was associated with areas of low sunlight exposure (p = 0.042) and the HLA-G expression with progression to death (p = 0.038). HLA-G expression was detected in MCC patients, as well as the MCPyV presence was confirmed. These markers could represent factors with a possible impact on patient survival; however, further studies with a greater number of patients are needed, to better elucidate the possible role in disease progression.

Different methods of cell quantification can lead to different results: a comparison of digital methods using a pilot study of dendritic cells in HIV-positive patients.

BACKGROUND: Although new digital pathology tools have improved the positive cell quantification, there is a heterogeneity of the quantification methods in the literature. The aim of this study was to evaluate and propose a novel dendritic cells quantification method in squamous cell carcinoma comparing it with a conventional quantification method. MATERIAL AND METHODS: Twenty-six squamous cell carcinomas HIV-positive cases affecting the oropharynx, lips and oral cavity were selected. Immunohistochemistry for CD1a, CD83, and CD207 was performed. The immunohistochemical stains were evaluated by automated examination using a positive pixel count algorithm. A conventional quantification method (unspecific area method; UA) and a novel method (specific area method; SA) were performed obtaining the corresponding density of positive dendritic cells for the intratumoral and peritumoral regions. The Mann-Whitney U test was used to verify the influence of the quantification methods on the positive cell counting according to the evaluated regions. Data were subjected to the ANOVA and Student's t-test to verify the influence of the tumour location, stage, histological grade, and amount of inflammation on the dendritic cells density counting. RESULTS: The cell quantification method affected the dendritic cells counting independently of the evaluated region (P-value <0.05). Significant differences between methods were also observed according to the tumour features evaluations. CONCLUSIONS: The positive cell quantification method influences the dendritic cells density results. Unlike the conventional method (UA method), the novel SA method avoids non-target areas included in the hotspots improving the reliability and reproducibility of the density cell quantification.

Multiresidue analysis and evaluation of the matrix effect on 20 pesticides in Brazilian maize (Zea mays L.) flour.

Maize consists of a cereal widely used in the preparation of different food products. Brazil is one of the world's largest maize producers. Several types of pesticides have been applied in maize crop, which can lead to the contamination of the derived products. The present work aims at the validation of multiresidue method to analyze the matrix effect and level of pesticides in maize flour. Twenty residues were investigated in samples commercialized in the state of Ceará, Brazil. The method was satisfactorily validated, according to parameters recommended by European Union. About 55% of the pesticides had an intense negative matrix effect. Multiresidue analyzes showed the presence of traces of fenitrotion in 20% of maize flour samples. Detected levels were below maximum residue limits recommended for maize. The results indicate that maize products need continuous monitoring to ensure food security.

Influence of apocynin on cardiac remodeling in rats with streptozotocin-induced diabetes mellitus.

BACKGROUND: Increased reactive oxygen species (ROS) generation in diabetes mellitus (DM) is an important mechanism leading to diabetic cardiomyopathy. Apocynin, a drug isolated from the herb Picrorhiza kurroa, is considered an antioxidant agent by inhibiting NADPH oxidase activity and improving ROS scavenging. This study analyzed the influence of apocynin on cardiac remodeling in diabetic rats. METHODS: Six-month-old male Wistar rats were assigned into 4 groups: control (CTL, n = 15), control + apocynin (CTL + APO, n = 20), diabetes (DM, n = 20), and diabetes + apocynin (DM + APO, n = 20). DM was induced by streptozotocin. Seven days later, apocynin (16 mg/kg/day) or vehicle was initiated and maintained for 8 weeks. Left ventricular (LV) histological sections were used to analyze interstitial collagen fraction. NADPH oxidase activity was evaluated in LV samples. Comparisons between groups were performed by ANOVA for a 2 × 2 factorial design followed by the Bonferroni post hoc test. RESULTS: Body weight (BW) was lower and glycemia higher in diabetic animals. Echocardiogram showed increased left atrial diameter, LV diastolic diameter, and LV mass indexed by BW in both diabetic groups; apocynin did not affect these indices. LV systolic function was impaired in DM groups and unchanged by apocynin. Isovolumic relaxation time was increased in DM groups; transmitral E/A ratio was higher in DM + APO compared to DM. Myocardial functional evaluation through papillary muscle preparations showed impaired contractile and relaxation function in both DM groups at baseline conditions. After positive inotropic stimulation, developed tension (DT) was lower in DM than CTL. In DM + APO, DT had values between those in DM and CTL + APO and did not significantly differ from either group. Myocardial interstitial collagen fraction was higher in DM than CTL and did not differ between DM + APO and CTL + APO. Serum activity of antioxidant enzymes glutathione peroxidase, superoxide dismutase (SOD), and catalase was lower in DM than CTL; apocynin restored catalase and SOD levels in DM + APO. Myocardial NADPH oxidase activity did not differ between groups. CONCLUSION: Apocynin restores serum antioxidant enzyme activity despite unchanged myocardial NADPH oxidase activity in diabetic rats.

Localized Magnetic Moments with Tunable Spin Exchange in a Gas of Ultracold Fermions.

We report on the experimental realization of a state-dependent lattice for a two-orbital fermionic quantum gas with strong interorbital spin exchange. In our state-dependent lattice, the ground and metastable excited electronic states of ^{173}Yb take the roles of itinerant and localized magnetic moments, respectively. Repulsive on-site interactions in conjunction with the tunnel mobility lead to spin exchange between mobile and localized particles, modeling the coupling term in the well-known Kondo Hamiltonian. In addition, we find that this exchange process can be tuned resonantly by varying the on-site confinement. We attribute this to a resonant coupling to center-of-mass excited bound states of one interorbital scattering channel.

Is There a Relationship Between Optimal Cerebral Perfusion Pressure-Guided Management and PaO2/FiO2 Ratio After Severe Traumatic Brain Injury?

OBJECTIVE: Severe traumatic brain injury (TBI) management has been associated with adult respiratory distress syndrome (ARDS) in previous literature. We aimed to investigate the relationships between optimal CPP-guided management, ventilation parameters over time and outcome after severe TBI. MATERIALS AND METHODS: We performed retrospective analysis of recorded data from 38 patients admitted to the NCCU after severe TBI, managed with optimal cerebral perfusion pressure (CPPopt)-guided therapy, calculated using pressure reactivity index (PRx). All patients were sedated and ventilated with lung protective criteria (Peep > 5, tidal volume 6-8 ml/kg and airway pressure < 30 cmH2O). RESULTS: Daily mean CPPopt varied between a minimum of 84 mmHg and a maximum of 91 mmHg with an all period mean value of 88 mmHg. The mean value for the difference between CPP and CPPopt was -1.9 mmHg. Daily mean P/F ratio decreased and varied between 253 and 387 with an all-period mean of 294 mmHg. During the 10 days of recording data, five patients (13%) developed criteria of severe ARDS, but only two patients died due to severe ARDS (5%). PaO2/FiO2 (P/F) ratio did not correlate with CPPopt, but showed a strong correlation with tidal volume (p = 0.000) and driving pressure (p = 0.000). CONCLUSIONS: Although CPPopt-guided therapy may induce a decrease in P/F ratio over time during the first 10 days, we could not find an association with worst outcome, which may be influenced by lung protective ventilation strategies and preservation of cerebral autoregulation.

Effects of glucosamine supplements on painful temporomandibular joint osteoarthritis: A systematic review.

The purpose of this study was to systematically review the literature for studies that assessed the effects of glucosamine supplements (GS) on pain and maximum mouth opening (MMO) restriction compared to other therapies, placebo or no intervention on painful temporomandibular joint osteoarthritis (TMJ OA). Randomised controlled trials were selected in a two-phase process. Seven electronic databases, in addition to three grey literature databases, were searched. Risk of bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Twelve potentially eligible studies were identified, from which three were finally included. Furthermore, two were categorised at low risk and one at high risk of bias. Intervention groups were treated with glucosamine-sulphate, while controls were treated with placebo or ibuprofen. In two studies, GS were equally effective regarding pain reduction and mouth opening improvement compared to ibuprofen taken two or three times a day over 12 weeks; however, one study did not find significant differences in follow-up evaluations concerning these clinical variables in both glucosamine and placebo groups administered over six weeks. There is very low evidence regarding GS therapeutic effects on TMJ OA. Considering a follow-up of 12 weeks, GS were as effective as ibuprofen taken two or three times a day. However, over six weeks of medication intake, GS were not superior to placebo. Still, included studies presented major drawbacks, and therefore, conclusions must be interpreted with caution.

Benign oral vascular lesions treated by sclerotherapy with ethanolamine oleate: A retrospective study of 43 patients.

BACKGROUND: Although sclerotherapy is a common treatment for benign oral vascular lesions, there is no well-standardized protocol for this purpose. The aim of the present study was to describe the clinical characteristics of patients treated by sclerotherapy with ethanolamine oleate (EO), in order to contribute to a better understanding of this technique. MATERIAL AND METHODS: Medical records and images of 90 patients treated by the same sclerotherapy protocol were retrieved and analysed. Thus, 43 cases with complete information were selected and described. RESULTS: The most affected age group was 41-70 years, with a female predominance and 86% of patients being Caucasian. Lips were the most affect site (70%) followed by the tongue (16%). Regarding clinical appearance, approximately 90% of lesions were classified as nodules, and 90% of patients reported no pain. Approximately 40% of lesions were 0.5-1.0 cm in size. In 58% of the patients, only one application of ethanolamine oleate was necessary. The application doses varied according to the lesion size and number of applications. Complete clinical regression occurred in 91% of cases, whereas 9% showed partial regression. CONCLUSIONS: Sclerotherapy with EO is an acceptable, effective and affordable treatment for benign oral vascular lesions.

Inhibition of proliferation and invasion in 2D and 3D models by 2-methoxyestradiol in human melanoma cells.

Despite the recent advances in the clinical management of melanoma, there remains a need for new pharmacological approaches to treat this cancer. 2-methoxyestradiol (2ME) is a metabolite of estrogen that has shown anti-tumor effects in many cancer types. In this study we show that 2ME treatment leads to growth inhibition in melanoma cells, an effect associated with entry into senescence, decreased pRb and Cyclin B1 expression, increased p21/Cip1 expression and G2/M cell cycle arrest. 2ME treatment also inhibits melanoma cell growth in colony formation assay, including cell lines with acquired resistance to BRAF and BRAF+MEK inhibitors. We further show that 2ME is effective against melanoma with different BRAF and NRAS mutational status. Moreover, 2ME induced the retraction of cytoplasmic projections in a 3D spheroid model and significantly decreased cell proliferation in a 3D skin reconstruct model. Together our studies bring new insights into the mechanism of action of 2ME allowing melanoma targeted therapy to be further refined. Continued progress in this area is expected to lead to improved anti-cancer treatments and the development of new and more effective clinical analogues.

Apocynin influence on oxidative stress and cardiac remodeling of spontaneously hypertensive rats with diabetes mellitus.

PURPOSE: Although increased oxidative stress is a major component of diabetic hypertensive cardiomyopathy, research into the effects of antioxidants on cardiac remodeling remains scarce. The actions of antioxidant apocynin include inhibiting reactive oxygen species (ROS) generation by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and ROS scavenging. We evaluated the effects of apocynin on cardiac remodeling in spontaneously hypertensive rats (SHR) with diabetes mellitus (DM). METHODS: Male SHR were divided into four groups: control (SHR, n = 16); SHR treated with apocynin (SHR-APO; 16 mg/kg/day, added to drinking water; n = 16); diabetic SHR (SHR-DM, n = 13); and SHR-DM treated with apocynin (SHR-DM-APO, n = 14), for eight weeks. DM was induced by streptozotocin (40 mg/kg, single dose). Statistical analyzes: ANOVA and Tukey or Mann-Whitney. RESULTS: Echocardiogram in diabetic groups showed higher left ventricular and left atrium diameters indexed for body weight, and higher isovolumetric relaxation time than normoglycemic rats; systolic function did not differ between groups. Isolated papillary muscle showed impaired contractile and relaxation function in diabetic groups. Developed tension was lower in SHR-APO than SHR. Myocardial hydroxyproline concentration was higher in SHR-DM than SHR, interstitial collagen fraction was higher in SHR-DM-APO than SHR-APO, and type III collagen protein expression was lower in SHR-DM and SHR-DM-APO than their controls. Type I collagen and lysyl oxidase expression did not differ between groups. Apocynin did not change collagen tissue. Myocardial lipid hydroperoxide concentration was higher in SHR-DM than SHR and SHR-DM-APO. Glutathione peroxidase activity was lower and catalase higher in SHR-DM than SHR. Apocynin attenuated antioxidant enzyme activity changes in SHR-DM-APO. Advanced glycation end-products and NADPH oxidase activity did not differ between groups. CONCLUSION: Apocynin reduces oxidative stress independently of NADPH oxidase activity and does not change ventricular or myocardial function in spontaneously hypertensive rats with diabetes mellitus. The apocynin-induced myocardial functional impairment in SHR shows that apocynin actions need to be clarified during sustained chronic pressure overload.

International multi-center evaluation of a novel chemiluminescence assay for the detection of anti-dsDNA antibodies.

OBJECTIVE: Anti-double stranded desoxyribonucleic acid (anti-dsDNA) antibodies are considered fairly specific for systemic lupus erythematosus (SLE) and their quantification is useful for the clinical management of SLE patients. We assessed the diagnostic performance of the QUANTA Flash dsDNA chemiluminescent immunoassay (CIA) in comparison to an ELISA, using patients from five participating countries. The main focus was to evaluate the correlation between anti-dsDNA antibody results from the CIA and global SLE disease activity, as measured by the SLE Disease Activity Index 2000 (SLEDAI-2K). PATIENTS AND METHODS: A total of 1431 samples (SLE, n = 843; disease controls, n = 588) from five countries (Canada, USA, Portugal, Sweden and Spain) were tested with QUANTA Flash dsDNA (Inova Diagnostics, San Diego, CA, USA). Data obtained with the QUANTA Lite dsDNA SC ELISA (Inova Diagnostics) were available for samples from three sites (Canada, USA and Sweden, n = 566). The SLEDAI-2K scores were available for 805 SLE patients and a cut-off of > 4 was used to define active disease. RESULTS: QUANTA Flash dsDNA had a sensitivity of 54.3% for the diagnosis of SLE, combined with 89.8% specificity. Anti-dsDNA antibody levels were significantly higher (p < 0.0001) in active SLE (SLEDAI-2K > 4; n = 232; median value 83.0 IU/mL) versus the inactive patients (n = 573; median value 22.3 IU/mL), and the SLEDAI-2K scoring correlated with their dsDNA antibody levels (Spearman's rho = 0.44, p < 0.0001). Similar but less pronounced findings were also found for the ELISA, in relation to disease activity. CONCLUSIONS: The QUANTA Flash dsDNA assay showed good clinical performance in a large international multi-center study. Additionally, the strong correlation between anti-dsDNA antibody results and SLEDAI-2K scores supported the potential utility of QUANTA Flash dsDNA for monitoring disease activity.

Reduced productivity among confined laying hens infested by Allopsoroptoides galli (Mironov, 2013).

The mite Allopsoroptoides galli has recently been identified parasitizing commercial chickens, São Paulo State/Brasil, causing severe dermatitis on all parts of the animal's body and a significant decline in productivity, particularly in egg production. The aim of the present study in A. galli infestation was to investigate the impact on laying hens' performance and egg quality. A total of 100 56-week-old Hy-line white laying hens were used. The birds were divided into 2 groups, with 10 replicates of 5 birds in each group. The experimental groups consisted of a non-infested group (hens free of theA. galli) and an infested group (hens presenting A. galli). The infestation with A. galli did not significantly influence feed intake but caused a significant reduction in the body weight of the hens and caused a decrease in egg production, therefore promoting worse feed conversion. The egg weight was reduced; however, the infestation did not significantly affect the internal quality of the eggs, which was measured according to the yolk color, albumen height, and Haugh units, or the quality of the shell, based on its percentage, thickness, and strength. It can be concluded that anA. galli infestation promotes a reduction in body weight, egg production, and egg weight in laying hens, therefore worsening feed conversion.

Observation of an Orbital Interaction-Induced Feshbach Resonance in (173)Yb.

We report on the experimental observation of a novel interorbital Feshbach resonance in ultracold (173)Yb atoms. This opens up the possibility of tuning the interactions between the (1)S(0) and (3)P(0) metastable state, both possessing zero total electronic angular momentum. The resonance is observed at experimentally accessible magnetic field strengths and occurs universally for all hyperfine state combinations. We characterize the resonance in the bulk via interorbital cross thermalization as well as in a three-dimensional lattice using high-resolution clock-line spectroscopy. Our measurements are well described by a generalized two-channel model of the orbital-exchange interactions.

A 3D printed microliquid jet with an adjustable nozzle diameter.

Microliquid jets have many applications, in particular in the fields of spectroscopy/analysis of samples susceptible to beam damage. Herein, we report a microliquid jet, manufactured with 3D printing technology, with a tuneable nozzle diameter output. This strategy increases the breadth of techniques that can be covered with a single microliquid jet.

How gamma-rays and electron-beam irradiation would affect the antimicrobial activity of differently processed wild mushroom extracts?

AIMS: The effects of irradiation (gamma-rays and electron-beams), up to 10 kGy, in the antimicrobial activity of mushroom species (Boletus edulis, Hydnum repandum, Macrolepiota procera and Russula delica) differently processed (fresh, dried, freeze) were evaluated. METHODS AND RESULTS: Clinical isolates with different resistance profiles from hospitalized patients in Local Health Unit of Mirandela, Northeast of Portugal, were used as target micro-organisms. The mushrooms antimicrobial activity did not suffer significant changes that might compromise applying irradiation as a possible mushroom conservation technology. CONCLUSIONS: Two kGy dose (independently of using gamma-rays or electron-beams) seemed to be the most suitable choice to irradiate mushrooms. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides important results in antimicrobial activity of extracts prepared from irradiated mushroom species.

Longitudinal reference range for umbilical cord cross-sectional area in twin pregnancies at 18-32 weeks of gestation.

OBJECTIVES: The objectives of this study were to establish gestational age-specific reference ranges for cross-sectional area of the umbilical cord, and its components, in twin pregnancies and to compare them with previously reported singleton reference ranges. METHODS: This was a prospective longitudinal study involving uncomplicated dichorionic twin pregnancies. Sonographic measurements of the cross-sectional area of the umbilical cord, umbilical vein and arteries and Wharton's jelly were obtained in a plane adjacent to the fetal abdomen, every 3 weeks, between 18 and 32 weeks of gestations. Multilevel regression analysis was used to determine gestational age-specific reference ranges for each parameter, and these were plotted against singleton pregnancy references. RESULTS: Three hundred and thirty four ultrasound scans were performed in 44 twin pregnancies, between 18 and 32.9 weeks (mean: 3.8 ± 0.7 scans/pregnancy and mean interval between scans: 3.3 ± 0.9 weeks). All umbilical cord cross-sectional areas (total, vein, artery and Wharton's jelly) showed a significant increase with gestational age. Compared with singleton pregnancy ranges, mean values were considerably lower in twin pregnancies and resemble the lower limits observed in singletons. CONCLUSION: In twin pregnancies, cross-sectional area of the umbilical cord, and its components, increases between 18 and 32 weeks, and mean values are substantially lower compared with singleton pregnancies.

Simvastatin Protects Osteoblasts from the Deleterious Effects of the Liquid Milieu of Multiple Myeloma.

Lytic bone lesions are the main clinical manifestation of multiple myeloma. The intense variety in this cell microenvironment, composed mainly of fibroblasts, osteoblasts, osteoclasts, immune cells and mesenchymal cells, is influenced by the massive presence of neoplastic plasma cells. Studies with statins have reported their action in stimulating the formation and reducing bone resorption. The aim of this study was to verify the in vitro response of human osteoblasts exposed to the supernatant (liquid milieu) of multiple myeloma. The data obtained indicate that simvastatin has positive effects on the growth of osteoblasts and protection against the anti-proliferative effects of multiple myeloma supernatant.

Periodontitis increases vascular cyclooxygenase-2: potential effect on vascular tone.

BACKGROUND AND OBJECTIVE: It has been demonstrated that periodontitis induces a systemic inflammation, which may impair endothelial function. Cyclooxygenase-2 (COX-2) is an important enzyme in the inflammatory process and is responsible for prostacyclin production. We hypothesised that in periodontitis, an increase in vascular COX-2 expression may occur, which in turn may have a role in vascular homeostasis. Thus, we evaluated the vascular effects of COX-2 inhibition in an experimental rat model of periodontitis. MATERIAL AND METHODS: Experimental periodontitis was induced in rats by placing a cotton ligature around the cervix of both sides of the mandibular first molars and maxillary second molars. Sham-operated rats had the ligature removed immediately after the procedure. Mesenteric vessels were obtained for the study of COX-2 expression, and blood samples were collected for nitric oxide quantification. In another set of experiments, animals received etoricoxib (10 mg/kg/d, v.o.) or vehicle, and alveolar bone loss and cardiovascular parameters were evaluated. RESULTS: We observed an increase in COX-2 expression in mesenteric vessels harvested from animals with periodontitis, which was accompanied by a reduction in nitric oxide content. Etoricoxib treatment impaired the endothelium-dependent reduction in blood pressure in rats with periodontitis. CONCLUSION: Periodontitis increases vascular COX-2 expression, which is important in the maintenance of vascular homeostasis in this model. Despite the limitations of an animal study, these findings may have important implications regarding the safety of using selective COX-2 inhibitors in patients with periodontitis.

The effect of simvastatin on systemic inflammation and endothelial dysfunction induced by periodontitis.

BACKGROUND AND OBJECTIVE: It has been demonstrated that periodontitis induces systemic inflammation, which may impair endothelial function leading to increased cardiovascular risk. The aim of this study was to evaluate the effect of simvastatin on systemic inflammatory markers and endothelial dysfunction induced by periodontitis. MATERIAL AND METHODS: Wistar rats were subjected to ligature-induced experimental periodontitis. Eight days after the procedure, the ligature and sham groups were randomly assigned to receive simvastatin or vehicle once a day until the 14th day, when the effects of acetylcholine and sodium nitroprusside on blood pressure were evaluated. Blood samples were collected and evaluated for plasma interleukin-6C, -reactive protein and lipids. The maxilla and mandible were removed for bone loss analysis. RESULTS: Simvastatin treatment reduced systemic inflammation and endothelial dysfunction induced by periodontitis. Furthermore, simvastatin improved the blood lipid profile and reduced alveolar bone loss. CONCLUSION: Simvastatin treatment, in addition to the improvement on serum lipid profile, may reduce other predictors of cardiovascular events associated with periodontitis.

Gastrointestinal amyloidosis in Australian indigenous patients.

This study documents the symptoms, racial distribution, pathological findings and outcomes of patients diagnosed with gastrointestinal amyloidosis in Alice Springs Hospital. In a 4 year retrospective survey. 9 patients, all indigenous, 7F/2M, had biopsy proven gastrointestinal amyloidosis. Four out of four patients tested were found to have AA amyloidosis. Presenting symptoms included diarrhoea, bloody in some, vomiting and abdominal pain. All but one had diabetes mellitus, type 2. Multiple infections were common and most patients had low serum albumin and transferrin concentrations but high serum ferritin concentrations. Five of the patients died, and the gastrointestinal symptoms of the remaining 4 remitted. Gastrointestinal amyloidosis should be included in the differential diagnosis of indigenous patients presenting with chronic diarrhoea, vomiting or abdominal pain. It carries a grave prognosis, is probably secondary to chronic infections but is potentially reversible.