High Iron and Iron Household Protein Contents in Perineuronal Net-Ensheathed Neurons Ensure Energy Metabolism with Safe Iron Handling.

A subpopulation of neurons is less vulnerable against iron-induced oxidative stress and neurodegeneration. A key feature of these neurons is a special extracellular matrix composition that forms a perineuronal net (PN). The PN has a high affinity to iron, which suggests an adapted iron sequestration and metabolism of the ensheathed neurons. Highly active, fast-firing neurons-which are often ensheathed by a PN-have a particular high metabolic demand, and therefore may have a higher need in iron. We hypothesize that PN-ensheathed neurons have a higher intracellular iron concentration and increased levels of iron proteins. Thus, analyses of cellular and regional iron and the iron proteins transferrin (Tf), Tf receptor 1 (TfR), ferritin H/L (FtH/FtL), metal transport protein 1 (MTP1 aka ferroportin), and divalent metal transporter 1 (DMT1) were performed on Wistar rats in the parietal cortex (PC), subiculum (SUB), red nucleus (RN), and substantia nigra (SNpr/SNpc). Neurons with a PN (PN+) have higher iron concentrations than neurons without a PN: PC 0.69 mM vs. 0.51 mM, SUB 0.84 mM vs. 0.69 mM, SN 0.71 mM vs. 0.63 mM (SNpr)/0.45 mM (SNpc). Intracellular Tf, TfR and MTP1 contents of PN+ neurons were consistently increased. The iron concentration of the PN itself is not increased. We also determined the percentage of PN+ neurons: PC 4%, SUB 5%, SNpr 45%, RN 86%. We conclude that PN+ neurons constitute a subpopulation of resilient pacemaker neurons characterized by a bustling iron metabolism and outstanding iron handling capabilities. These properties could contribute to the low vulnerability of PN+ neurons against iron-induced oxidative stress and degeneration.

The MTP1 promoters from Arabidopsis halleri reveal cis-regulating elements for the evolution of metal tolerance.

In the hyperaccumulator Arabidopsis halleri, the zinc (Zn) vacuolar transporter MTP1 is a key component of hypertolerance. Because protein sequences and functions are highly conserved between A. halleri and Arabidopsis thaliana, Zn tolerance in A. halleri may reflect the constitutively higher MTP1 expression compared with A. thaliana, based on copy number expansion and different cis regulation. Three MTP1 promoters were characterized in A. halleri ecotype I16. The comparison with the A. thaliana MTP1 promoter revealed different expression profiles correlated with specific cis-acting regulatory elements. The MTP1 5' untranslated region, highly conserved among A. thaliana, Arabidopsis lyrata and A. halleri, contains a dimer of MYB-binding motifs in the A. halleri promoters absent in the A. thaliana and A. lyrata sequences. Site-directed mutagenesis of these motifs revealed their role for expression in trichomes. A. thaliana mtp1 transgenic lines expressing AtMTP1 controlled by the native A. halleri promoter were more Zn-tolerant than lines carrying mutations on MYB-binding motifs. Differences in Zn tolerance were associated with different distribution of Zn among plant organs and in trichomes. The different cis-acting elements in the MTP1 promoters of A. halleri, particularly the MYB-binding sites, are probably involved in the evolution of Zn tolerance.

Bone-block arthrodesis procedure in failures of first metatarsophalangeal joint replacement.

BACKGROUND: The treatment for the failure of a first metatarsophalangeal joint (MTP1) prosthesis can be complex. There is no consensus regarding the ideal treatment. One of the main issues is the available bone stock after prosthesis removal. The aim of the study was to report the clinical and radiographic results for MTP1 arthrodesis with autologous calcaneus bone graft (bone-block fusion) as a revision procedure of a previous MTP1 implant failure. METHODS: This study included 12 patients diagnosed with failure of a MTP1 prosthesis. All patients were treated with MTP1 arthrodesis using ipsilateral calcaneal bone graft. Patients were evaluated with the Foot Ankle Disability Index (FADI), the visual analogue pain scale (VAS) and AOFAS Hallux Metatarsophalangeal Interphalangeal scoring system (AOFAS-HMI), weight-bearing radiograph of the foot, and a computed tomography scan. The 1-2 intermetatarsal angle, hallux valgus angle, and first ray length were measured before surgery and at final follow-up. RESULTS: Complications included 3 cases of arthrodesis nonunion, (1 symptomatic, 2 asymptomatic) with 2 of the 3 patients experiencing hardware failure and 1 superficial wound infection. The average FADI improved from 41.8 preoperatively to 84.6 at final follow-up (p<0.05); the average VAS improved from 8.5 preoperatively to 2 at final follow-up (p<0,05); the average AOFAS-HMI significantly improved from 50.7 preoperatively to 73.8 at final follow-up (p<0.05). The average length of the bone-block used was 14.3mm (range 11-19mm). The 1-2 intermetatarsal angle decreased from 9.5° preoperatively to 8.4° at final follow-up (p<0.05); hallux valgus angle improved from 19.7° preoperatively to 14.3° at final follow-up (p<0.05). CONCLUSIONS: The management of a failed first metatarsophalangeal joint prosthesis remains controversial. Bone-block arthrodesis using ipsilateral calcaneal autograft appears to be a viable option restoring the bone loss, and avoiding hallux shortening. Nonunion is the most frequent complication with 25% of patients affected, but only 1/3 of patients with nonunion were symptomatic and required revision.

The Rotoglide™ total replacement of the first metatarso-phalangeal joint. A prospective series with 7-15 years clinico-radiological follow-up with survival analysis.

BACKGROUND: The Rotoglide total replacement of the MTP-1 joint. 15 years survival analysis. The purpose of this prospective study was to evaluate the long-term performance clinico-radiographically of an uncemented three-component total replacement for the first metatarso-phalangeal joint (MTP-1) used for hallux rigidus (primary osteoarthritis grades 3 and 4). The follow-up was median 11.5 years (7-15). METHODS: The AOFAS forefoot score was used preoperatively and at follow-up. Radiographs were taken weight-bearing in the AP-projection and in tip-toe standing in the lateral view. Arthrosis in the sesamoid junction, prosthetic loosening, subsidence (of prosthesis as well as sesamoids), and dorsiflexion were measured, recorded and subjected to multiple variance analysis. Survival analysis was performed for 15 years. MATERIAL: Ninety implants in 80 patients (53 women and 27 men); median age 58 (41-76) were evaluated. RESULTS: Six patients representing seven prostheses in situ had died from unrelated reason. The median preoperative AOFAS increased significantly from 40 to 95. The median gain was 45. Four replacements (4.4%) were extracted for other reasons than loosening. No aseptic loosenings were recorded. The survival rate at 15 years was 91.5% (83-100). Multiple variance analysis showed that arthrosis in the metatarso-sesamoid junction correlated with reduced AOFAS score. CONCLUSION: The prosthesis has stood the test of time; the results justify its further use.

Characterization of the histidine-rich loop of Arabidopsis vacuolar membrane zinc transporter AtMTP1 as a sensor of zinc level in the cytosol.

The vacuolar Zn(2+)/H(+) antiporter of Arabidopsis thaliana, AtMTP1, has a long cytosolic histidine-rich loop. A mutated AtMTP1 in which the first half of the loop (His-half) was deleted exhibited a 11-fold higher transport velocity in yeast cells. Transgenic lines overexpressing the His-half-deleted AtMTP1 in the loss-of-function mutant were evaluated for growth and metal content in the presence of various zinc concentrations. These overexpressing lines (35S-AtMTP1 and 35S-His-half lines) showed high tolerance to excess concentrations of zinc at 150 µM, as did the wild type, compared with the loss-of-function line. The His-half AtMTP1 transported cobalt in a heterologous expression assay in yeast, but the cumulative amount of cobalt in 35S-His-half plants was not increased. Moreover, the accumulation of calcium and iron was not changed in plants. Under zinc-deficient conditions, growth of 35S-His-half lines was markedly suppressed. Under the same conditions, the 35S-His-half lines accumulated larger amounts of zinc in roots and smaller amounts of zinc in shoots compared with the other lines, suggesting an abnormal accumulation of zinc in the roots of 35S-His-half lines. As a result, the shoots may exhibit zinc deficiency. Taken together, these results suggest that the His-loop acts as a sensor of cytosolic zinc to maintain an essential level in the cytosol and that the dysfunction of the loop results in an uncontrolled accumulation of zinc in the vacuoles of root cells.

Silicone Arthroplasty as an Alternative to Arthrodesis in the Metatarsophalangeal Degenerative Disease of Hallux Valgus-A 5-Year Observational Study.

Background: Arthroplasty is gaining more and more popularity in the treatment of osteoarthritis (OA) of the metatarsophalangeal I joint (MTP1). The aim of our study was to evaluate the early and long-term objective clinical and radiographic results, as well as the subjective results, of MTP1 arthroplasty in comparison to MTP1 arthrodesis among patients with OA and a valgus deformity of their MTP 1 joint. Methods: Patients with OA MTP1 were examined before surgery and in the 5-year period after surgery. The inclusion criteria for the study were OA of the MTP1 joint and a non-axial position of the toe in valgus between 20 and 40 degrees. Prostheses were created for the patients with higher demands for mobility of their MTP 1 joint and arthrodesis was carried out for those with lower expectations. The treatment outcomes were assessed by clinical examination, radiography, the AOFAS scale, the SEFAS scale, and using patient-related outcome measures (PROM). Results: A total of 39 people, 37 women and 2 men, aged 55 to 67 years old (average, 61 years old) participated in the study. During the follow-up period, there were no complications in the form of infection or a loosening of the implant after both arthroplasty and arthrodesis. The follow-up examination 60 months after the surgery showed an improvement in scores (>20 points) on both the AOFAS and SEFAS scales. All patients, after surgery, reported reduced pain. Conclusions: The use of a silicone prosthesis in the surgical treatment of degenerative changes in the MTPI joint, with appropriate indications and excluding cases with large hallux valgus, gives better results than arthrodesis.

Effect of lag screw on stability of first metatarsophalangeal joint arthrodesis with medial plate.

Background: First metatarsophalangeal joint (MTP-1) arthrodesis is a commonly performed procedure in the treatment of disorders of the great toe. Since the incidence of revision after MTP-1 joint arthrodesis is not insignificant, a medial approach with a medially positioned locking plate has been proposed as a new technique. The aim of the study was to investigate the effect of the application of a lag screw on the stability and strength of first metatarsophalangeal joint arthrodesis with medial plate. Methods: The bending tests in a testing machine were performed for models of the first metatarsal bone and the proximal phalanx printed on a 3D printer from polylactide material. The bones were joined using the locking titanium plate and six locking screws. The specimens were divided into three groups of seven each: medial plate and no lag screw, medial plate with a lag screw, dorsal plate with a lag screw. The tests were carried out quasi-static until the samples failure. Results: The addition of the lag screw to the medial plate significantly increased flexural stiffness (41.45 N/mm vs 23.84 N/mm, p = 0.002), which was lower than that of the dorsal plate with a lag screw (81.29 N/mm, p < 0.001). The similar maximum force greater than 700 N (p > 0.50) and the relative bone displacements lower than 0.5 mm for a force of 50 N were obtained for all fixation techniques. Conclusions: The lag screw significantly increased the shear stiffness in particular and reduced relative transverse displacements to the level that should not delay the healing process for the full load of the MTP-1 joint arthrodesis with the medial plate. It is recommended to use the locking screws with a larger cross-sectional area of the head to minimize rotation of the medial plate relative to the metatarsal bone.

Non-union incidence of different joint preparation types, joint fixation techniques, and postoperative weightbearing protocols for arthrodesis of the first metatarsophalangeal joint in moderate-to-severe hallux valgus: a systematic review.

Purpose: A systematic review to determine the effect of different types of joint preparation, joint fixation, and postoperative weight-bearing protocols on non-union frequency in first metatarsophalangeal joint (MTPJ) arthrodesis in patients with moderate-to-severe hallux valgus. Material and methods: A systematic literature search (PubMed and EMBASE), adhering to PRISMA guidelines. Data on MTPJ preparation, fixation, weight-bearing, and non-union in patients with moderate-to-severe hallux valgus were collected. Quality assessment was performed using the Coleman Methodology Score. Results: Sixteen studies (934 feet) were included, generally of medium quality. Overall non-union rate was 7.7%. At 6.3%, convex/concave joint preparation had the lowest non-union rate vs 12.2% for hand instruments and 22.2% for planar cuts. Non-union of 2.8% was found for joint fixation with a plate combined with a lag screw vs 6.5% for plate fixation, 11.1% for crossed screw fixation, and 12.5% for a plate with a cross plate compression screw. A 5.1% non-union frequency was found following postoperative full weight-bearing on a flat shoe vs 9.3% for full weight-bearing on a heel weight-bearing shoe and 0% for a partial weight-bearing regimen. Conclusion: Based on medium-quality papers, joint preparation with convex/concave reamers and joint fixation with a plate using a lag screw show the lowest non-union rate. Full postoperative weight-bearing in a stiff-soled postoperative shoe is safe and not associated with non-union vs a more protective load-bearing regimen. Further research should focus on larger sample sizes, longer follow-ups, and stronger study designs.

RNA interference-mediated hookworm control by gut-dwelling lactic acid bacteria.

Background: The complex life cycle of geohelminth parasites make it difficult to manage repeated infections that occur in endemic areas, that requires the development of new therapeutic strategies. Human hookworm Ancylostoma sp. and Necator sp. are a serious problem in many areas of the world where the old age anti-helminthics are ineffective. To address this, we have tried a non-traditional therapeutic approach for a sustainable solution to manage parasite infections. Aims and Objectives: In this study, we attempted to develop a new type of therapy using value-added probiotics-producing antiparasitic RNA interference (RNAi) molecules against a vital hookworm (Ancylostoma sp.) enzyme, astacin-like metalloprotease Ac-MTP-1. A new gut delivery RNAi vector was designed to produce double-stranded RNA (dsRNA) against the target to be delivered by feeding with a probiotic Lactococcus lactis that when administered in endemic areas can potentially be used to control the spread of infection by interrupting the life cycle of hookworm. Results: The engineered probiotics colonizing the gut, when consumed by the parasite released the dsRNA that which knocked down the target by RNAi interfering with their moulting and tissue migration. The initial penetration of the larvae into the gut lining was reduced by 70%, followed by a reduction of up to 50% in migration to the critical organs. The damage caused to the liver (30%-40%) and the kidneys (50%-60%) by the hookworm in mouse models as quantitated by enzymes released in the blood was totally reversed when the worms were pre fed with the engineered L. lactis before the parasite challenge. Conclusions: We believe that this is the first demonstrated knockdown of a target gene in hookworms using probiotics genetically engineered to stimulate RNAi (RNAi food), administered through the oral route. This novel method of parasite control when extended to other hookworms, A. duodenalis and A. ceylanicum can augment the efficacy of the existing anthelminthics if combined with them.

Five-Year Prospective Roentgen Stereophotogrammetric and Clinical Outcomes of the BioPro MTP-1 Hemiarthroplasty.

BACKGROUND: Mixed results for functional outcomes and long-term fixation have been reported for first metatarsophalangeal arthroplasty. This prospective study was designed to evaluate the migration of the BioPro metatarsophalangeal-1 (MTP-1) joint hemiprosthesis with Roentgen stereophotogrammetric analysis (RSA). Migration patterns of the prosthesis, prosthesis-induced erosion of the metatarsal bone, and clinical outcomes were evaluated sequentially to 5 years postoperation (PO). METHODS: Eleven female patients received the BioPro-1 hemiprosthesis. Prosthesis translation and metatarsal erosion were measured with RSA at immediately PO, 6 weeks, and 3, 6, 12, 36, and 60 months postoperatively. Clinical assessment was done by patient questionnaires. RESULTS: RSA data of 9 patients were available for analysis. Median (range) number of markers used in RSA analysis, condition number, and mean error of markers around the prosthesis were 4 (3-7), 320 (208-862), and 0.13 (0.02-0.28), respectively. Progressive subsidence was seen up to 3 years PO (mean 2.1 mm, SE 0.32). Progressive metatarsal erosion was found from 1 year PO (mean 0.49 mm, SE 0.15). Pain, function, and quality scores improved after surgery and did not deteriorate at later follow-up moments. CONCLUSION: Model-based RSA of the BioPro-1 prosthesis shows nonstabilizing medial and distal translation and metatarsal erosion. Despite the measured migration and erosion, clinical outcomes improved and remained similar up to 5 years postoperation. LEVEL OF EVIDENCE: Level II, prospective analysis of MTP-1 hemiprosthesis.

Gait Analysis of Foot Compensation After Arthrodesis of the First Metatarsophalangeal Joint.

BACKGROUND: Arthrodesis of the first metatarsophalangeal (MTP1) joint is an intervention often used in patients with severe MTP1 joint osteoarthritis and relieves pain in approximately 80% of these patients. The kinematic effects and compensatory mechanism of the foot for restoring a more normal gait pattern after this intervention are unknown. The aim of this study was to clarify this compensatory mechanism, in which it was hypothesized that the hindfoot and forefoot would be responsible for compensation after an arthrodesis of the MTP1 joint. METHODS: Gait properties were evaluated in 10 feet of 8 patients with MTP1 arthrodesis and were compared with 21 feet of 12 healthy subjects. Plantar pressures and intersegmental range of motion were measured during gait by using the multisegment Oxford Foot Model. Pre- and postoperative X-rays of the foot and ankle were also evaluated. RESULTS: The MTP1 arthrodesis caused decreased eversion of the hindfoot during midstance, followed by an increased internal rotation of the hindfoot during terminal stance, and ultimately more supination and less adduction of the forefoot during preswing. In addition, MTP1 arthrodesis resulted in a lower pressure time integral beneath the hallux and higher peak pressures beneath the lesser metatarsals. A mean dorsiflexion fusion angle of 30 ± 5.4 degrees was observed in postoperative radiographs. CONCLUSION: This study demonstrated that the hindfoot and forefoot compensated for the loss of motion of the MTP1 joint after arthrodesis in order to restore a more normal gait pattern. This resulted in a gait in which the rigid hallux was less loaded while the lesser metatarsals endured higher peak pressures. Further studies are needed to investigate whether this observed transfer of load or a preexistent decreased compensatory mechanism of the foot can possibly explain the disappointing results in the minority of the patients who experience persistent complaints after a MTP1 arthrodesis. LEVEL OF EVIDENCE: Level III, comparative series.

The mechanism of iron transport after intratracheal instillation of iron in rats.

OBJECTIVES: Iron (Fe) is an essential element in biological processes; however excessive Fe is harmful to human health. Some air pollutants contain a high level of Fe, and the human lung could therefore be over-exposed to Fe through inhaled air pollutants. This study was performed to investigate the role of metal transporters (divalent metal transporter 1, DMT1, and metal transporter protein 1, MTP1) in the lung under the environments of Fe deficiency in the body and Fe over-exposure in the lung. METHODS: Rats were fed Fe deficient (FeD, 2-6 mg Fe/kg) or Fe supplemented (FeS, 120 mg Fe/kg) diet for 4 weeks, followed by a single intratracheal instillation of ferrous sulfate at low (10 mg/kg) or high (20 mg/kg) dose. Fe concentration was analyzed in the serum, lung and liver, and histopathological findings were observed in the lung at 24 hours after Fe administration. The level of DMT1 and MTP1 expression in the lung was analyzed by RT-PCR. Also, the effect of Fe deficiency in the body was evaluated on the level of Fe concentration and metal transporters compared to FeS-diet fed rats at the end of 4-week FeD or FeS diet. RESULTS: The 4-week FeD diet in rats induced an Fe deficiency anemia with decreased serum total Fe, increased unsaturated Fe binding capacity and hypochromic microcytic red blood cells. The concentration of Fe in the lung and liver was lower in the FeD-diet fed rats than in the FeS-diet fed rats. The level of metal transporters mRNA expression was higher in the FeD-diet fed rats than in the FeS-diet. The concentration of Fe in the lung was increased in a dose-dependent pattern after intratracheal instillation of Fe into the rats, while the level of Fe in the serum and liver was not increased in the low-dose Fe administered rats. Therefore, DMT1 and MTP1 mRNA was highly expressed in both FeD-diet and FeS-diet fed rats, after intratracheal instillation of Fe. CONCLUSIONS: DMT1 and MTP1 mRNA were more highly expressed in FeD-diet fed rats than in FeS-diet fed rats. The over-exposure of Fe intratracheally induced high expression of metal transporters and increased Fe deposition in the lung in both FeD-diet and FeS-diet fed rats, but did not increase the Fe level of the serum and liver in low-dose Fe administered rats. These results suggest that the role of metal transporters in the lung might be different in a part from the duodenum under the environment of over-exposure to Fe.