Design and functionality of a prototype for cold needle perforation of wheat

Wheat is a vital crop in global food security, but up to 25% of the wheat harvested is contaminated with mycotoxins that have detrimental effects on human health. To address this issue, biological detoxification strategies have been developed using microorganisms and enzymes. Perforating the whole wheat kernel using cold needle perforation (CNP) followed by a detoxification step could be a promising approach to reduce cross-contamination during the milling of mycotoxin-containing wheat. In this study, a pilot-scale CNP prototype was developed to perforate wheat kernels, and its effectiveness was evaluated. The height-adjustable perforation unit consists of 3120 needles. The throughput of the CNP prototype was adjusted to 6 kg/h, and the kernels were perforated for 1, 5, or 10 cycles. The results show that the CNP prototype effectively perforates wheat kernels, as evidenced by the significant increase in pore count. Fluorescence microscopy confirmed the penetration of particles in the size range of enzymes and microorganisms into the kernel. This study demonstrates the successful scale-up of CNP for wheat kernel perforation and highlights the potential of CNP as a cost-effective and efficient method for the biological detoxification of mycotoxin-contaminated wheat

Extradural Synovial Cyst of the Cervical Spine in a Saint Bernard

Background: Extradural synovial cysts (ESC) originate from an extrusion of the synovium in unstable or degenerated joints. In the spine, this condition can cause neurological signs such as hyperesthesia, proprioceptive ataxia and paresis. Since extradural presentations of synovial cysts are unusual in dogs, the aim of this manuscript is to report a case of extradural synovial cyst of the cervical spine, as well as the clinical findings, diagnosis, surgical treatment and clinical evolution after therapy.Case: A 3-year-old spayed Saint Bernard weighing 60 kg was presented to a Veterinary Medical Teaching Hospital with a history of acute paraparesis that evolved to non-ambulatory tetraparesis five days after the appearance of the first clinical signs. Neurological examination revealed non-ambulatory tetraparesis, normal muscle tone and segmental spinal reflexes in the thoracic and pelvic limbs, as well as cervical pain associated with limited neck movement. According to the neurological examination, the likely lesion location was the C1-C5 spinal cord segment. The differential diagnosis list included intervertebral disc disease, caudal cervical spondylomyelopathy, neoplasm, infectious or noninfectious inflammatory disease, and cystic diseases. Complete blood (cell) count and serum biochemistry tests were within reference limits. The cerebrospinal fluid analysis revealed 35 mg/dL of protein (< 30 mg/dL) and 27 cells (up to 5 cells/mm3) with a predominance of lymphocytes. In plain radiography, bone proliferations of the C4 (caudal) C5 (cranial) articular processes were observed and, in myelography, extradural spinal cord compression was evident between C4-C5 on the right side. The animal underwent dorsal laminectomy for spinal cord decompression. An extradural synovial cyst and proliferated articular processes were removed. At 1,281 days after surgery, the dog was clinically normal and presented no neurological deficits.Discussion: The etiology of synovial cysts has not been well established. However, it is believed that osteoarthritic degeneration associated with joint mobility could cause a rupture in the articular capsule, leading to a synovial membrane protrusion, which would fill with synovial fluid and compress spinal structures. ESC in the cervical region have been reported, often associated with cervical neoplasm. The case we report had no evidence of bone or intervertebral disc compression in myelographic and radiographic exams, abnormalities that would appear in cervical neoplasm. The patient underwent dorsal laminectomy to confirm the presumptive diagnosis and decompress the spine. In the histopathological exam, the cystic material consisted of connective fibrous tissue with a synovial cell lining layer, compatible with synovial cysts. The fluid drained during surgery was also analyzed, showing similarities to synovial fluid drained from other conventional joints. Cerebrospinal fluid analysis revealed mononuclear pleocytosis, a common finding in ESC. The ESC should be included in the differential diagnosis of dogs with cervical myelopathy, especially in young animals and large breeds. A myelographic exam is an important but not definitive auxiliary tool for diagnosis and the therapeutic plan. Dorsal laminectomy is an effective technique for treating ESC

Postoperative Analgesia with Transdermal Fentanyl or Intramuscular Methadone in Dogs Submitted to Thoracolumbar Hemilaminectomy

Background: Postoperative care after thoracolumbar hemilaminectomy in dogs generally includes rest, physical therapy, and analgesics such as opioids. Currently, there is no established standard for the management of postoperative pain in patients undergoing hemilaminectomy. Ideally, an analgesic protocol should provide adequate pain relief with limited sedation, low adverse effects, and postoperative patient comfort. Therefore, this study aimed to evaluate postoperative analgesia using transdermal fentanyl or intramuscular methadone in dogs undergoing thoracolumbar hemilaminectomy associated with intervertebral disc fenestration (HT) for the treatment of intervertebral disc extrusion (IVDE).Materials, Methods &amp; Results: Eight dogs from the Department of Neurology and Neurosurgery of a veterinary teaching hospital, submitted to HT for the treatment of IVDE, were included. The dogs were randomly distributed into two groups of equal numbers, namely the transdermal fentanyl (FT) group and the intramuscular methadone (IM) group. At the end of the surgical procedure, a fentanyl adhesive patch was applied to the animals in the FT group, which remained there for 72 h. In the IM group, analgesia was induced by intramuscular administration of methadone at intervals of 6 h until 72 h after surgery. The animals were evaluated using the short form of the Glasgow Composite Pain Scale (SF-GCPS). Evaluations of physiological parameters, side effects, and pain were performed by two assessors who had experience using the pain scale and were blinded to the analgesic protocol. Pain evaluations were performed every 2 h (from T4) until 24 h after the surgical procedure. Evaluations were performed every 4 h from 24 h to 48 h after the surgical procedure and at intervals of 24 h from 48 h to 72 h.Discussion: Transdermal fentanyl provided the lowest pain scores, when evaluated by the SF-GCPS, for both assessors. These data are presented as a function of time in Figure 1, which shows the variation in pain scores by SF-GCPS over time. It should be noted that, for both assessors, animals in the FT group had lower pain scores than animals in the IM group. There was also less variation in pain scores in the FT group, indicating better analgesic quality. This can be explained by the maintenance of the drug’s plasma concentrations in a stable manner, avoiding periods of greater or lesser pain throughout the evaluation period due to the absence of increases or decreases in plasma concentration. In the IM group, three analgesic rescues were required; in the FT group, there was no rescue. Although the data indicate that IM was responsible for a greater occurrence in the number of rescues, it is worth noting that this information is based on a small group of animals. One dog needed two rescues (at T4 and T8), regarding which both assessors agreed, while another required one rescue (at T18), but there was a difference of one point between the raters. However, pain scores in all of the cases were considered to be mild, not moderate or severe, with rescues occurring on scores of 5/20. Both fentanyl used by the transdermal route and intramuscular methadone promoted analgesia in the first three postoperative days in dogs undergoing HT. Better stability in postoperative pain scores without the need for analgesic rescue and less occurrence of adverse effects were observed in dogs treated with FT.Keywords: fentanyl patch, neurosurgery, dogs, analgesia, pain.Título: Analgesia pós-operatória com Fentanil transdérmico ou Metadona intramuscular em cães submetidos à hemilaminectomia toracolombar Descritores: adesivo fentanil, neurocirurgia, cães, analgesia, dor

Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers

Introduction: Bulevirtide is a first-in-class antiviral drug to treat chronic hepatitis B/D. We investigated the drug-drug interaction potential and pharmacokinetics of high-dose subcutaneous bulevirtide (5 mg twice daily) with organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (CYP) 3A4.Methods: This was a single-center, open-label, fixed-sequence drug-drug interaction trial in 19 healthy volunteers. Before and at bulevirtide steady state, participants ingested a single 40 mg dose of pravastatin. A midazolam microdose was applied to quantify CYP3A4 activity.Results: At bulevirtide steady state, pravastatin area under the concentration-time curve (AUC0–∞) increased 1.32-fold (90% CI 1.08-1.61). The 5 mg bulevirtide twice-daily treatment resulted in a mean AUC0-12 of 1210 h*ng/ml (95% CI 1040-1408) and remained essentially unchanged under the influence of pravastatin. CYP3A4 activity did not change to a clinically relevant extent. As expected, total bile acids increased substantially (35-fold) compared to baseline during bulevirtide treatment. All study medication was well tolerated.Discussion: The study demonstrated that high-dose bulevirtide inhibited OATP1B-mediated hepatic uptake of the marker substrate pravastatin but the extent is considered clinically not relevant. Changes in CYP3A4 activity were also not clinically relevant. In conclusion, this study suggests that OATP1B substrate drugs as well as CYP3A4 substrates may safely be used without dose adjustment in patients treated with bulevirtide. However, in patients using high statin doses and where concomitant factors potentially further increase statin exposure, caution may be required when using bulevirtide

Intradural Disc Extrusion in a Dog

Background: Intervertebral disc extrusion is an important cause of spinal cord dysfunction in dogs. Intradural localization of the extruded disc material is rare, and is generally associated with a traumatic event or with recurrence of disc extrusion at a previously affected site. We report the clinical presentation, diagnostic workup, and treatment of a dog with intradural intervertebral disc extrusion not preceded by a traumatic event.Case:  A 6-year-old male Dachshund was referred for neurological evaluation due to acute onset of hind-end paralysis preceded by claudication of the left hindlimb. The patient had been receiving conservative treatment to no effect. Neurological examination revealed asymmetric non-ambulatory paraparesis, absence of postural reactions and decreased muscle tone in both hindlimbs, a bilaterally diminished patellar reflex, and a hindlimb withdrawal reflex which was normal on the right and greatly diminished to absent on the left. The lower back was tender to epaxial palpation. Plain radiographs of the lumbar spine in the lateral projection showed calcified material within the spinal canal between the third and fourth lumbar vertebrae. Myelography was suggestively abnormal at the same level, with epidural leakage of contrast at L3-L4. Considering the clinical history, breed, age, neurological signs, and radiographic findings, intervertebral disc disease was suspected despite the inconclusive myelography findings. A dorsolateral lumbar hemilaminectomy was performed. Intraoperatively, the diagnosis was confirmed by visualization of a discolored spinal cord and absence of extradural material. The intradural space was accessed via durotomy. A firm, straw-yellow material was seen compressing the spinal cord and removed. Subsequent histopathological examination confirmed that this material consisted of extruded intervertebral disc contents. Postoperatively, the patient underwent physiotherapy and achieved a satisfactory recovery.Discussion: The most common cause of paraparesis in chondrodystrophic dog breeds is intervertebral disc extrusion. Intradural extrusion of the intervertebral disc is a rare phenomenon, often associated with vigorous exercise that causes laceration of the dura mater, allowing penetration of disc material into the intradural space. Although there were no classic signs of intervertebral disc disease on plain radiography, radiopaque material was visible within the spinal canal, which can occur in cases of calcified intervertebral disc extrusion. Myelography was inconclusive, but the decision was made to operate nevertheless, considering that the patient had not responded to conservative treatment and that surgicaltreatment is the most suitable approach for dogs with non-ambulatory paraparesis or paraplegia secondary to intervertebral disc extrusion. The surgical technique consisted of a hemilaminectomy and durotomy. Our diagnostic suspicion was confirmed intraoperatively, as in most cases of intradural disc extrusion in humans. Intradural disc extrusion is anuncommon phenomenon in dogs, and the diagnosis is usually only established intraoperatively. This unusual variant of intravertebral disc disease should be included in the differential diagnosis of spinal cord dysfunction in chondrodystrophic breeds, even in the absence of a history of trauma or preexisting intervertebral disc disease. Clinical treatment appears ineffective in these cases. Conversely, surgical treatment can yield good outcomes, and even functional recovery

Study of exclusive one-pion and one-eta production using hadron and dielectron channels in pp reactions at kinetic beam energies of 1.25 GeV and 2.2 GeV with HADES

We present measurements of exclusive ensuremathπ+,0 and η production in pp reactions at 1.25GeV and 2.2GeV beam kinetic energy in hadron and dielectron channels. In the case of π+ and π0 , high-statistics invariant-mass and angular distributions are obtained within the HADES acceptance as well as acceptance-corrected distributions, which are compared to a resonance model. The sensitivity of the data to the yield and production angular distribution of Δ (1232) and higher-lying baryon resonances is shown, and an improved parameterization is proposed. The extracted cross-sections are of special interest in the case of pp → pp η , since controversial data exist at 2.0GeV; we find \ensuremathσ=0.142±0.022 mb. Using the dielectron channels, the π0 and η Dalitz decay signals are reconstructed with yields fully consistent with the hadronic channels. The electron invariant masses and acceptance-corrected helicity angle distributions are found in good agreement with model predictions

PD-1 Regulates Neural Damage in Oligodendroglia-Induced Inflammation

We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system

Temporal Pattern of ICAM-I Mediated Regulatory T Cell Recruitment to Sites of Inflammation in Adoptive Transfer Model of Multiple Sclerosis

Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development