Nitric oxide and hormesis.

This present paper provides an assessment of the occurrence of nitric oxide (NO)-induced hormetic-biphasic dose/concentration relationships in biomedical research. A substantial reporting of such NO-induced hormetic effects was identified with particular focus on wound healing, tumor promotion, and sperm biology, including mechanistic assessment and potential for translational applications. Numerous other NO-induced hormetic effects have been reported, but require more development prior to translational applications. The extensive documentation of NO-induced biphasic responses, across numerous organs (e.g., bone, cardiovascular, immune, intestine, and neuronal) and cell types, suggests that NO-induced biological activities are substantially mediated via hormetic processes. These observations are particularly important because broad areas of NO biology are constrained by the quantitative features of the hormetic response. This determines the amplitude and width of the low dose stimulation, affecting numerous biomedical implications, study design features (e.g., number of doses, dose spacing, sample sizes, statistical power), and the potential success of clinical trials.

Low-dose radiation therapy (LDRT) for COVID-19 and its deadlier variants.

Coronavirus variants are gaining strongholds throughout the globe. Despite early signals that SARS-CoV-2 coronavirus case numbers are easing up in the United States and during the middle of a (not so easy) vaccination roll out, the country has passed a grim landmark of 600,000 deaths. We contend that these numbers would have been much lower if the medical community undertook serious investigations into the potential of low doses of radiation (LDRT) as a mainstream treatment modality for COVID-19 pneumonia. LDRT has been posited to manifest anti-infectious and anti-inflammatory properties at doses of 0.3-1.0 Gy via the activation of the Nrf-2 pathway. Although some researchers are conducting well-designed clinical trials on the potential of LDRT, the deep-rooted, blind, and flawed acceptance of the Linear No-Threshold (LNT) model for ionizing radiation has led to sidelining of this promising therapy and thus unimaginable numbers of deaths in the United States.

Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases.

The voltage-gated potassium (Kv) 1.3 channel is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases. ShK-186, a selective inhibitor of Kv1.3 channels, ameliorates autoimmune diseases in rodent models, and human phase 1 trials of this agent in healthy volunteers have been completed. In this study, we identified and characterized a large family of Stichodactyla helianthus toxin (ShK)-related peptides in parasitic worms. Based on phylogenetic analysis, 2 worm peptides were selected for study: AcK1, a 51-residue peptide expressed in the anterior secretory glands of the dog-infecting hookworm Ancylostoma caninum and the human-infecting hookworm Ancylostoma ceylanicum, and BmK1, the C-terminal domain of a metalloprotease from the filarial worm Brugia malayi. These peptides in solution adopt helical structures closely resembling that of ShK. At doses in the nanomolar-micromolar range, they block native Kv1.3 in human T cells and cloned Kv1.3 stably expressed in L929 mouse fibroblasts. They preferentially suppress the proliferation of rat CCR7(-) effector memory T cells without affecting naive and central memory subsets and inhibit the delayed-type hypersensitivity (DTH) response caused by skin-homing effector memory T cells in rats. Further, they suppress IFNγ production by human T lymphocytes. ShK-related peptides in parasitic worms may contribute to the potential beneficial effects of probiotic parasitic worm therapy in human autoimmune diseases.

Successful Renal Transplant in End-Stage Renal Disease with Chronic Immune Thrombocytopenia using Thrombopoietin Receptor Agonists and Intravenous Immunoglobulin.

Chronic kidney disease in immune thrombocytopenia (ITP) is uncommon, and renal transplant in this setting is rare. We discuss the successful renal transplant of a 29-year-old male with chronic ITP. During transplant, he was managed with thrombopoietin receptor agonist eltrombopag, intravenous methylprednisone, and intravenous immunoglobulin to maintain adequate platelet level. He recovered well with no major complications and good graft function and has been stable during the follow-up period. The case report highlights that renal transplantation is a feasible option in patients with ITP, even in the presence of low platelet counts.

An Unusual Case of Metastatic Prostate Cancer Presenting as a Massive Urinoma.

Urinoma formation as the first manifestation of carcinoma prostate is uncommon and has been reported only twice in the literature. We report a case of prostatic carcinoma in an elderly man who first presented in the emergency department with left-sided abdominal pain. His radiological investigations revealed a left-sided urinoma with dilatation of the entire ureter and an enlarged prostate with areas of varied intensity especially in the peripheral zone of the left lobe. In view of raised serum prostate-specific antigen (PSA) (155 ng/ml), a prostate biopsy was done, which showed features of adenocarcinoma (Gleason score 5+5). He was managed with pigtail drainage of urinoma, followed by double J stenting of the left ureter, and later underwent bilateral orchidectomy to reduce tumor burden, being metastatic disease. The stent was removed at a later date.

Experimental Investigation and Optimization of Electric Discharge Machining Process Parameters Using Grey-Fuzzy-Based Hybrid Techniques.

Electrical discharge machining (EDM) has recently been shown to be one of the most successful unconventional machining methods for meeting the requirements of today's manufacturing sector by producing complicated curved geometries in a broad variety of contemporary engineering materials. The machining efficiency of an EDM process during hexagonal hole formation on pearlitic Spheroidal Graphite (SG) iron 450/12 grade material was examined in this study utilizing peak current (I), pulse-on time (Ton), and inter-electrode gap (IEG) as input parameters. The responses, on the other hand, were the material removal rate (MRR) and overcut. During the experimental trials, the peak current ranged from 32 to 44 A, the pulse-on duration ranged from 30-120 s, and the inter-electrode gap ranged from 0.011 to 0.014 mm. Grey relational analysis (GRA) was interwoven with a fuzzy logic method to optimize the multi-objective technique that was explored in this EDM process. The effect of changing EDM process parameter values on responses was further investigated and statistically analyzed. Additionally, a response graph and response table were produced to determine the best parametric setting based on the calculated grey-fuzzy reasoning grade (GFRG). Furthermore, predictor regression models for response characteristics and GFRG were constructed, and a confirmation test was performed using randomly chosen input parameters to validate the generated models.

Suture augmentation of acromioclavicular and coracoclavicular ligament reconstruction for acute acromioclavicular dislocation.

ABSTRACT: The objective of this report was to introduce a new suture augmentation of coracoclavicular (CC) and acromioclavicular ligament reconstruction for acute Rockwood grade III to V acromioclavicular dislocations.From January 2015 to January 2019, 43 patients with Rockwood III to VI acute acromioclavicular dislocations were retrospectively reviewed. For comparison, another series of 28 patients treated with double Endobutton technique from January 2011 to December 2014 were reviewed. A P < .05 was considered statistical significance.The mean follow-up period of the 2 series were 39.69 ±â€Š7.42 months (range, 24-54 months) and 37.86 ±â€Š8.23 months (range, 26-48 months) (P > .05), respectively. There were significant differences regarding CC space (11.62 ±â€Š2.54 mm vs 16.78 ±â€Š5.53 mm; P < .05), CC reduction loss (5.56 ±â€Š4.73 mm vs 26.25 ±â€Š4.42 mm; P < .05), and acromioclavicular space (6.89 ±â€Š1.87 mm vs 7.95 ±â€Š2.37 mm; P < .05). There were significant differences regarding the disabilities of the arm, shoulder, and hand questionnaire (3.3 ±â€Š2.8 vs 5.32 ±â€Š4.37; P < .05) and University of California-Los Angeles shoulder rating scale (31.19 ±â€Š2.48 vs 29.24 ±â€Š2.48; P < .05). The excellent to good percentages were 100% (n = 32) and 85% (n = 23), respectively.In conclusion, the suture augmentation of acromioclavicular and CC ligament reconstruction is a reliable technique for acute acromioclavicular dislocation with minimal complications.Type of study/level of evidence: Therapeutic IIa.

Modulation of Lymphocyte Potassium Channel KV1.3 by Membrane-Penetrating, Joint-Targeting Immunomodulatory Plant Defensin.

We describe a cysteine-rich, membrane-penetrating, joint-targeting, and remarkably stable peptide, EgK5, that modulates voltage-gated KV1.3 potassium channels in T lymphocytes by a distinctive mechanism. EgK5 enters plasma membranes and binds to KV1.3, causing current run-down by a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. EgK5 exhibits selectivity for KV1.3 over other channels, receptors, transporters, and enzymes. EgK5 suppresses antigen-triggered proliferation of effector memory T cells, a subset enriched among pathogenic autoreactive T cells in autoimmune disease. PET-CT imaging with 18F-labeled EgK5 shows accumulation of the peptide in large and small joints of rodents. In keeping with its arthrotropism, EgK5 treats disease in a rat model of rheumatoid arthritis. It was also effective in treating disease in a rat model of atopic dermatitis. No signs of toxicity are observed at 10-100 times the in vivo dose. EgK5 shows promise for clinical development as a therapeutic for autoimmune diseases.

Cardiac cells implanted into a cylindrical, vascularized chamber in vivo: pressure generation and morphology.

We have previously described a model to implant dissociated cells into a cylindrical, vascularized bed in vivo to promote the formation of functional cardiac muscle constructs. We now investigate the cellular organization and the ability of the constructs to generate intra-luminal pressure. Primary cardiac cells were isolated from hearts of 2-3 day old rats, suspended in fibrin gel and inserted into the lumen of silicone tubing. The silicone tubing was then implanted around the femoral vessels in the groin region of recipient animals. After 3 weeks, the constructs were harvested, placed in an in vitro bath and cannulated via the incorporated femoral artery with a pressure transducer for evaluation of intra-luminal pressure dynamics. Histological evaluation showed the presence of a concentric ring of cardiac cells surrounding the femoral vessels. There was also a significant amount of collagen present around cardiac cells. In addition, we observed a significant amount of neovascularization of the explanted constructs. Electron microscopy showed the presence of longitudinally aligned fibers with a large number of gap junctions. Upon electrical stimulation of a single pulse (7 V, 1.2 ms), the constructs generated an intra-luminal pressure of 1.19 +/- 0.45 mmHg (n = 6). In addition, we were able to electrically pace the constructs at frequencies of 0.5-5 Hz. A Starling behavior of the inverse relation between baseline pressure and twitch pressure was observed. Cardiac cells implanted for 3 weeks into the cylindrical vascularized bed formed a tissue construct that demonstrated many of the contractile properties and morphology expected of functioning cardiac tissues.

A randomized comparison of bone-cement K-wire fixation vs. plate fixation of shaft fractures of proximal phalanges.

BACKGROUND: The objective of this study (ClinicalTrials.gov ID: NCT03031015) is to compare the treatments of hand proximal phalanx shaft fractures with external-fixation technique using the combination of K-wires and bone-cement vs. open reduction and internal fixation technique using a miniature plate-and-screw system. METHODS: A total of 107 patients (134 cases) were randomly allocated to group A (67 cases in 56 patients) and B (64 cases in 51 patients). Fingers in group A were treated with bone-cement K-wire fixation, and fingers in group B were treated using a plate-and-screw system. RESULTS: Follow-ups lasted 2 years. In group A, active range of motion of proximal interphalangeal joint reached 93% ± 6.7% of the opposite fingers. In group B, the data reached 86% ± 14.4% of the opposite fingers. Based on total active motion scoring system, we obtained 21 excellent and 46 good results in group A; and 9 excellent, 50 good, and 5 fair results in group B. There was a significant difference with regards to the function of the fingers (p < 0.05). CONCLUSIONS: The bone-cement K-wire fixation may be another option for the treatment of shaft fractures of proximal phalanges. The minimally invasive technique allows early joint motion, resulting in minimal complications and good functional recovery.

Using Tongue Depressors as a Technique to Aid Cord Localization During Collagenase Injection For Dupuytren Disease.

Collagenase injections are used as a minimally invasive treatment for Dupuytren contracture of the palm and fingers, with good published success. Most complications are related to injection-site swelling, pain, and ecchymosis. However, the risk of flexor tendon and digital nerve injury can occur when injecting cords that cause proximal interphalangeal joint contractures. In addition, poor localization and incorrect injection of the solution into cords may result in an incomplete correction. We describe a technique to improve visualization and isolation of Dupuytren cords using a tongue depressor.

Isolated Small Finger Distal Interphalangeal Joint Dupuytren's Contracture.

Dupuytren's contracture is a disease involving abnormal myofibroblast proliferation and collagen deposition leading to the formation of pathologic cords in the hand. Given that Dupuytren's contractures rarely extend to the distal interphalangeal joint (DIP), affecting only 5% of patients, there are few cases reported in the literature. Collagenase injection is a frequently used option for minimally invasive treatment of Dupuytren's disease with greater than a 20-degree joint contracture. Unfortunately, there is limited research on the effectiveness of these injections in isolated DIP joint deformities. We present a case of a 61-year-old right hand-dominant male with a 2-year history of isolated right small finger Dupuytren's contracture at the DIP joint who achieved significant improvement after collagenase injection.

Treatment of Bennett fractures with tension-band wiring through a small incision under loupes and a headlight.

PURPOSE: The aim of the study was to present a novel treatment strategy for Bennett fractures using a tension-band wiring technique performed through a small incision with loupes and a headlight. Additionally, this study compared this technique with the conventional percutaneous pinning technique. METHODS: Between January 2014 and January 2017, the tension-band wiring technique was used in 37 patients with Bennett fractures (study group). The range of motion, pinch and grip strengths, and hand function were assessed at the final follow-up. A control group comprising 35 patients treated with the percutaneous pinning technique was included in the study for comparison. A p-value <0.05 was considered statistically significant. (Clinical Trial Registration number: ISRCTN64894535 at http://www.isrctn.com/ISRCTN64894535 ) Results: No fixation failure or infection occurred in either group. Radiographic fracture healing was achieved in all cases. Follow-up lasted over 1 year. The mean Kapandji opposition score was 9.31 (range 8-10) points in the study group and 8.45 (range 7-10) points in the control group (p < 0.05). The mean Disabilities of the Arm, Shoulder, and Hand score was 1.06 (range 0-2) in the study group and 1.77 (range 0-3) in the control group (p < 0.05). The mean Smith and Cooney Score were 90 (range 80-100) in the study group and 85 (range 75-100) in the control group (p < 0.05). CONCLUSIONS: The tension-band wiring technique using loupes and headlights enables reduction and fixation of Bennett fractures under direct visualization of the deep operative field. Restoration of thumb function using the tension-band wiring technique is significantly better than that observed with the conventional percutaneous pinning technique.

Methodology for the formation of functional, cell-based cardiac pressure generation constructs in vitro.

We have previously described a model to engineer three-dimensional (3-D) heart muscle in vitro. In the current study, we extend our model of 3-D heart muscle to engineer a functional cell-based cardiac pressure generating construct (CPGC). Tubular constructs were fabricated utilizing a phase separation method with chitosan as the scaffolding material. Primary cardiac cells isolated from rat hearts were plated on the surface of fibrin gels cast in 35 mm tissue culture dishes. CPGCs (N = 8) were formed by anchoring the tubular constructs to the center of the plate with primary cardiac cells seeded in fibrin gels wrapped around the tubular constructs. Intraluminal pressure measurements were evaluated with and without external electrical stimulation and histological evaluation performed. The fibrin gel spontaneously compacted due to the traction force of the cardiac cells. By 14 d after original cell plating, the cardiac cells had completely formed a monolayer around the tubular construct resulting in the formation of a cell-based CPGC. The spontaneous contractility of the CPGC was macroscopically visible and resulted in intraluminal pressure spikes of 0.08 mmHg. Upon electrical stimulation, the CPGCs generated twitch pressures of up to 0.05 mmHg. In addition, the CPGC constructs were electrically paced at frequencies of up to 3 Hz. Histological evaluation showed the presence of a continuous cell monolayer around the surface of the tubular construct. In this study, we describe a novel in vitro method to engineer functional cell-based CPGCs and demonstrate several physiological metrics of functional performance.

Force characteristics of in vivo tissue-engineered myocardial constructs using varying cell seeding densities.

Experiments have been successfully performed culminating in functional, vascularized, three-dimensional cardiac muscle tissue. Past experience in tissue engineering has led us to the understanding that cell seeding density plays a critical role in the formation and function of both in vitro and in vivo engineered tissues. Therefore, to improve upon the mechanics of this model and to facilitate the formation of myocardial tissue with improved functional performance, we sought to optimize the seeding density of cardiomyocytes in these constructs. Neonatal cardiac myocytes were isolated from 2-day-old Fischer 344 rat hearts. Silicone chambers containing fibrin gel were seeded with varying numbers of cardiac cells (1, 5, 10, and 20 million). Control chambers were prepared using fibrin gel alone. All of the chambers were then implanted around the femoral vessels of isogenic rats. Six constructs per cell seeding density group were implanted. Histological and immunohistochemical evaluation was performed via hematoxylin and eosin, von Gieson, and alpha-sarcomeric actin staining protocols. Linear contractile force measurements were obtained for each construct following 4 weeks of in vivo implantation. After an implantation period of 4 weeks, the newly formed cardiac constructs contained within the chambers were harvested. The femoral vessels within the constructs were found to be patent in all cases. With direct electrical stimulation, the constructs were able to generate an average active force that varied depending on their seeding density. Constructs with seeding densities of 1, 5, 10, and 20 million cells produced an average active force of 208, 241, 151, and 108 microN, respectively. The control constructs did not generate any active force on electrical stimulation. This study demonstrates the in vivo survival, vascularization, organization, and function of transplanted myocardial cells. It is also apparent that cell seeding density plays a direct role in the force generation and mechanical properties of these engineered constructs. Among different groups using varying cell seeding densities, we found that the group with 5 million cells generated maximum active force.

Subcutaneous Ulnar Nerve Transposition Using Osborne's Ligament as a Ligamentodermal or Ligamentofascial Sling.

The ulnar nerve is most commonly compressed at the elbow in the cubital tunnel. Conservative and operative treatments have been applied for cubital tunnel syndrome. Surgical management options include decompression, medial epicondylectomy, and various anterior transposition techniques. We describe a novel technique of anterior transposition of the ulnar nerve by using Osborne's ligament as a sling to avoid subluxation. Osborne's ligament is incised posteriorly and medially on the olecranon to create a sling with 2 to 3 cm width. The sling is tailored to wrap around the ulnar nerve and attached to the flexor-pronator fascia or dermis to create a smooth gliding surface without causing compression. Ten patients with cubital tunnel syndrome, established by physical examination findings and electromyography/nerve conduction studies underwent ulnar nerve transposition using this technique and were able to participate in a phone survey. The average follow-up was 15.6 months (range, 4-28 months). The average time to become subjectively "better" after surgery was 4.2 weeks. The pain intensity was reduced from an average of 7.5 preoperatively to <1, on a 10-point scale, at the time of the survey. All patients had symptomatic relief without any complication. The proposed technique using Osborne's ligament as a ligamentofascial or ligamentodermal sling offers a unique way of creating a non-compressive sling with the component of the cubital tunnel itself and has an additional benefit of creating a smooth gliding surface for early return of function.

Structure, folding and stability of a minimal homologue from Anemonia sulcata of the sea anemone potassium channel blocker ShK.

Peptide toxins elaborated by sea anemones target various ion-channel sub-types. Recent transcriptomic studies of sea anemones have identified several novel candidate peptides, some of which have cysteine frameworks identical to those of previously reported sequences. One such peptide is AsK132958, which was identified in a transcriptomic study of Anemonia sulcata and has a cysteine framework similar to that of ShK from Stichodactyla helianthus, but is six amino acid residues shorter. We have determined the solution structure of this novel peptide using NMR spectroscopy. The disulfide connectivities and structural scaffold of AsK132958 are very similar to those of ShK but the structure is more constrained. Toxicity assays were performed using grass shrimp (Palaemonetes sp) and Artemia nauplii, and patch-clamp electrophysiology assays were performed to assess the activity of AsK132958 against a range of voltage-gated potassium (KV) channels. AsK132958 showed no activity against grass shrimp, Artemia nauplii, or any of the KV channels tested, owing partly to the absence of a functional Lys-Tyr dyad. Three AsK132958 analogues, each containing a Tyr in the vicinity of Lys19, were therefore generated in an effort to restore binding, but none showed activity against any of KV channels tested. However, AsK132958 and its analogues are less susceptible to proteolysis than that of ShK. Our structure suggests that Lys19, which might be expected to occupy the pore of the channel, is not sufficiently accessible for binding, and therefore that AsK132958 must have a distinct functional role that does not involve KV channels.

Neurotization improves contractile forces of tissue-engineered skeletal muscle.

Engineered functional skeletal muscle would be beneficial in reconstructive surgery. Our previous work successfully generated 3-dimensional vascularized skeletal muscle in vivo. Because neural signals direct muscle maturation, we hypothesized that neurotization of these constructs would increase their contractile force. Additionally, should neuromuscular junctions (NMJs) develop, indirect stimulation (via the nerve) would be possible, allowing for directed control. Rat myoblasts were cultured, suspended in fibrin gel, and implanted within silicone chambers around the femoral vessels and transected femoral nerve of syngeneic rats for 4 weeks. Neurotized constructs generated contractile forces 5 times as high as the non-neurotized controls. Indirect stimulation via the nerve elicited contractions of neurotized constructs. Curare administration ceased contraction in these constructs, providing physiologic evidence of NMJ formation. Histology demonstrated intact muscle fibers, and immunostaining positively identified NMJs. These results indicate that neurotization of engineered skeletal muscle significantly increases force generation and causes NMJs to develop, allowing indirect muscle stimulation.

A minimally invasive approach for cubital tunnel release and ulnar nerve transposition.

OBJECTIVES: The aim of the study is to introduce a new minimally invasive technique for ulnar nerve release and transposition. METHODS: From January 2010 to May 2011, 51 patients with cubital tunnel syndrome were treated through a 1.5 to 2 cm incision. Limb functional recovery, scar esthetics, sensitivity of scar, numbness of the operating area, and patient satisfaction were assessed. RESULTS: No wound hematoma nor infection was observed in the group. The time of operation was 36 ± 17.2 minutes. At the final follow-up of 63 ± 7.3 months, 2-point discrimination of the small finger was improved from 6.3 ± 2.2 mm to 5.2 ± 2.4 mm. Grip and pinch strength of the hand were improved from 14.2 ± 7.7 kg and 3.7 ± 2.4 kg to 35.2 ± 12.7 kg and 4.1 ± 2.8 kg, respectively. The motor nerve conduction velocity was improved from 36.5 ± 11.2 to 44.6 ± 6.7 (m/sec). The Disabilities of the Shoulder, Arm, and Hand questionnaire score was improved from 37.2 ± 23.8 to 10.5 ± 9.6. No patients reported scar pain, sensitivity of scar, or numbness of the operating area. No revision surgery was needed. Michigan Hand Outcome score for aesthetics was 94.6%±5.1 and satisfaction was 92 ± 8, respectively. We obtained 33 excellent, 12 good, 5 fair, and 1 poor result. CONCLUSION: Ulnar nerve decompression with anterior transposition can be safely and effectively accomplished through the small incision. It can be an alternative technique producing good appearance.

Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36): development of an anorectic Y4 receptor selective agonist with picomolar affinity.

We have previously shown [Cys-Trp-Arg-Nva-Arg-Tyr-NH(2)](2), 1, to be a moderately selective neuropeptide Y (NPY) Y(4) receptor agonist. Toward improving the selectivity and potency for Y(4) receptors, we studied the effects of dimerizing H-Trp-Arg-Nva-Arg-Tyr-NH(2) using various diamino-dicarboxylic acids containing either di-, tri-, or tetramethylene spacers. These parallel dimers, 2A, 2B, 3, 4A, and 4B, and the corresponding linear tandem dimer and trimer analogues, 5 and 6, had enhanced selectivity and affinity for Y(4) receptors compared to 1 (Table 1). Substitution of Trp and Nva with Tyr and Leu, respectively, as in 2,7-d/l-diaminosuberic acid derivatized dimer, 7, resulted in a superior Y(4) selective agonist with picomolar affinity. Intraperitoneal (ip) injection of 7 potently inhibited food intake in fasted mice. Moreover, 7 (ip) inhibited the food intake in wild-type mice and not in Y(4)(-/-) knock-out mice, confirming that the actions of 7 on food intake are not due to global effects, but specifically mediated Y(4) receptors.