Abnormal motoneuron migration, differentiation, and axon outgrowth in spinal muscular atrophy

The role of heterotopic (migratory) motoneurons (HMN) in the pathogenesis of spinal muscular atrophy (SMA) is still controversial. We examined the occurrence and amount of HMN in spinal cord tissue from eight children with SMA (six with SMA-I and two with SMA-II). All affected subjects were carrying a homozygous deletion of exon 7 in the SMN1 gene. Unlike controls, virtually free from HMN, all SMA subjects showed a significant number of HMN at all levels of the spinal cord. Heterotopic neurons were hyperchromatic, located mostly in the ventral white matter and had no axon or dendrites. More than half of the HMN were very undifferentiated, as judged from their lack of immunoreactivity for NeuN and MAP2 proteins. Small numbers of more differentiated heterotopic neurons were also found in the dorsal and lateral white matter region. As confirmed by ultrastructural analysis, in situ end labeling (ISEL) and CD68 immunoreactivity, HMN in the ventral outflow were found to have no synapses, to activate microglial cells, and to eventually die by necrosis. An unbiased quantitative analysis showed a significant negative correlation between age of SMA subjects (a reflection of the clinical severity) and the number of HMN. Subjects who died at older ages had increased number of GFAP-positive astrocytes. Complementing our previous report on motoneuron apoptosis within the ventral horns in SMA, we now propose that abnormal migration, differentiation, and lack of axonal outgrowth may induce motoneuron apoptosis predominantly during early stages, whereas a slower necrosis-like cell death of displaced motoneurons which "escaped" apoptosis characterizes later stages of SMA

Bypassing major venous occlusion and duodenal lesions in rats, and therapy with the stable gastric pentadecapeptide BPC 157, L-NAME and L-arginine

AIM: To investigate whether duodenal lesions induced by major venous occlusions can be attenuated by BPC 157 regardless nitric oxide (NO) system involvement. ----- METHODS: Male Wistar rats underwent superior anterior pancreaticoduodenal vein (SAPDV)-ligation and were treated with a bath at the ligated SAPDV site (BPC 157 10 μg, 10 ng/kg per 1 mL bath/rat; L-NAME 5 mg/kg per 1 mL bath/rat; L-arginine 100 mg/kg per 1 mL bath/rat, alone and/or together; or BPC 157 10 μg/kg instilled into the rat stomach, at 1 min ligation-time). We recorded the vessel presentation (filled/appearance or emptied/disappearance) between the 5 arcade vessels arising from the SAPDV on the ventral duodenum side, the inferior anterior pancreaticoduodenal vein (IAPDV) and superior mesenteric vein (SMV) as bypassing vascular pathway to document the duodenal lesions presentation; increased NO- and oxidative stress [malondialdehyde (MDA)]-levels in duodenum. ----- RESULTS: Unlike the severe course in the SAPDV-ligated controls, after BPC 157 application, the rats exhibited strong attenuation of the mucosal lesions and serosal congestion, improved vessel presentation, increased interconnections, increased branching by more than 60% from the initial value, the IAPDV and SMV were not congested. Interestingly, after 5 min and 30 min of L-NAME and L-arginine treatment alone, decreased mucosal and serosal duodenal lesions were observed; their effect was worsened at 24 h, and no effect on the collateral vessels and branching was seen. Together, L-NAME+L-arginine antagonized each other's response, and thus, there was an NO-related effect. With BPC 157, all SAPDV-ligated rats receiving L-NAME and/or L-arginine appeared similar to the rats treated with BPC 157 alone. Also, BPC 157 in SAPDV-ligated rats normalized levels of NO and MDA, two oxidative stress markers, in duodenal tissues. ----- CONCLUSION: BPC 157, rapidly bypassing occlusion, rescued the original duodenal flow through IAPDV to SMV flow, an effect related to the NO system and reduction of free radical formation

The Role of Pentadecapeptide BPC 157 and NO-system on Incisional Ventral Hernia Prevention and Wound Tensile Strength Impact

Dosadašnjim istraživanjima dokazano je pozitivno djelovanje BPC-a 157 na cijeljenje kožnih rana i mišićno-tetivnih oštećenja, no nije ispitan njegov utjecaj na prevenciju razvoja incizijskih hernija (IH). Ispitivao se utjecaj BPC-a 157, L-NAME-a i L-arginina na prevenciju razvoja IH-a, veličinu IH-a (VIH), prezentaciju kožnog ožiljka (PKO), trbušne priraslice (TP) i vlačnu čvrstoću rane (VČR) u četiri vremenske točke (7, 14, 21 i 28 dan) na štakorima soja Wistar kod kojih je induciran razvoj IH-a. Sukladno eksperimentalnome protokolu štakorima je kontinuirano davan BPC 157 (0,16 μg/mL ili 0,16 ng/mL, po.), L-NAME (5 mg/kg ip.), L-arginin (100 mg/kg ip.) te njihove kombinacije. BPC 157 smanjio je incidenciju IH-a (p(μg) < 0,0001, p(ng) < 0,0001) kao i VIH-a. Životinje tretirane L-NAME-om i L-argininom imale su veće IH od životinja iz kontrolne skupine. Životinje tretirane BPC-om 157 imale su urednu PKO, kao i manje TP, dok su životinje tretirane L-NAME-om, L-argininom te kombinacijom imale više TP. Životinje tretirane BPC-om 157 tijekom 28 dana imale su veću VČR (p(μg) = 0,0498, p(ng) = 0,0419). BPC 157 pokazao je preventivni učinak na razvoj i veličinu IH-a te pozitivan dugoročni učinak na VČR, što predstavlja potencijal primjene ovoga preparata u prevenciji razvoja IH-a.Positive BPC 157 effect on skin wounds and muscle-tendon is known. Effect on incisional hernia (IH) prevention has not been studied. BPC 157, L-NAME and L-arginineffect on IH development and IH size (IHS), cutaneous wound appearance (CWA), abdominal adhesions (AA) and tensile strength (TS) was monitored for 7, 14, 21, and 28 days on Wistar rats. Ratswere continuously treated with BPC 157 (0,16 μg/mL or 0,16 ng/mL, per os), L-NAME (5 mg/kg ip), L-arginin (100 mg/kg ip) and combinations. BPC 157 reduced the incidence of IH (p(μg) < 0,0001, p(ng) < 0,0001) as well as IHS. Animals treated with L-NAME and L-arginine had larger IHS than control group animals. Animals treated with BPC 157 differed in CWA- predominantly regular healing, as well as less AA, while animals treated with L-NAME, L-arginine and combination had more AA. Animals treated with BPC 157 for 28 days had greater TS (p(μg) = 0,0498, p(ng) = 0,0419). BPC 157 presented preventive effect on IH development, IHS, and long-term positive TS effect. This implies potential usage in IH prevention

Uloga pentadekapeptida BPC 157 i sustava NO u prevenciji incizijskih ventralnih hernija i njihov utjecaj na vlačnu čvrstoću rane [The Role of Pentadecapeptide BPC 157 and NO-system on Incisional Ventral Hernia Prevention and Wound Tensile Strength Impact]

Positive BPC 157 effect on skin wounds and muscle-tendon is known. Effect on incisional hernia (IH) prevention has not been studied. BPC 157, L-NAME and L-arginineffect on IH development and IH size (IHS), cutaneous wound appearance (CWA), abdominal adhesions (AA) and tensile strength (TS) was monitored for 7, 14, 21, and 28 days on Wistar rats. Ratswere continuously treated with BPC 157 (0,16 μg/mL or 0,16 ng/mL, per os), L-NAME (5 mg/kg ip), L-arginin (100 mg/kg ip) and combinations. BPC 157 reduced the incidence of IH (p(μg) < 0,0001, p(ng) < 0,0001) as well as IHS. Animals treated with L-NAME and L-arginine had larger IHS than control group animals. Animals treated with BPC 157 differed in CWA- predominantly regular healing, as well as less AA, while animals treated with L-NAME, L-arginine and combination had more AA. Animals treated with BPC 157 for 28 days had greater TS (p(μg) = 0,0498, p(ng) = 0,0419). BPC 157 presented preventive effect on IH development, IHS, and long-term positive TS effect. This implies potential usage in IH prevention

The Role of Pentadecapeptide BPC 157 and NO-system on Incisional Ventral Hernia Prevention and Wound Tensile Strength Impact

Dosadašnjim istraživanjima dokazano je pozitivno djelovanje BPC-a 157 na cijeljenje kožnih rana i mišićno-tetivnih oštećenja, no nije ispitan njegov utjecaj na prevenciju razvoja incizijskih hernija (IH). Ispitivao se utjecaj BPC-a 157, L-NAME-a i L-arginina na prevenciju razvoja IH-a, veličinu IH-a (VIH), prezentaciju kožnog ožiljka (PKO), trbušne priraslice (TP) i vlačnu čvrstoću rane (VČR) u četiri vremenske točke (7, 14, 21 i 28 dan) na štakorima soja Wistar kod kojih je induciran razvoj IH-a. Sukladno eksperimentalnome protokolu štakorima je kontinuirano davan BPC 157 (0,16 μg/mL ili 0,16 ng/mL, po.), L-NAME (5 mg/kg ip.), L-arginin (100 mg/kg ip.) te njihove kombinacije. BPC 157 smanjio je incidenciju IH-a (p(μg) < 0,0001, p(ng) < 0,0001) kao i VIH-a. Životinje tretirane L-NAME-om i L-argininom imale su veće IH od životinja iz kontrolne skupine. Životinje tretirane BPC-om 157 imale su urednu PKO, kao i manje TP, dok su životinje tretirane L-NAME-om, L-argininom te kombinacijom imale više TP. Životinje tretirane BPC-om 157 tijekom 28 dana imale su veću VČR (p(μg) = 0,0498, p(ng) = 0,0419). BPC 157 pokazao je preventivni učinak na razvoj i veličinu IH-a te pozitivan dugoročni učinak na VČR, što predstavlja potencijal primjene ovoga preparata u prevenciji razvoja IH-a.Positive BPC 157 effect on skin wounds and muscle-tendon is known. Effect on incisional hernia (IH) prevention has not been studied. BPC 157, L-NAME and L-arginineffect on IH development and IH size (IHS), cutaneous wound appearance (CWA), abdominal adhesions (AA) and tensile strength (TS) was monitored for 7, 14, 21, and 28 days on Wistar rats. Ratswere continuously treated with BPC 157 (0,16 μg/mL or 0,16 ng/mL, per os), L-NAME (5 mg/kg ip), L-arginin (100 mg/kg ip) and combinations. BPC 157 reduced the incidence of IH (p(μg) < 0,0001, p(ng) < 0,0001) as well as IHS. Animals treated with L-NAME and L-arginine had larger IHS than control group animals. Animals treated with BPC 157 differed in CWA- predominantly regular healing, as well as less AA, while animals treated with L-NAME, L-arginine and combination had more AA. Animals treated with BPC 157 for 28 days had greater TS (p(μg) = 0,0498, p(ng) = 0,0419). BPC 157 presented preventive effect on IH development, IHS, and long-term positive TS effect. This implies potential usage in IH prevention

The Role of Pentadecapeptide BPC 157 and NO-system on Incisional Ventral Hernia Prevention and Wound Tensile Strength Impact

Dosadašnjim istraživanjima dokazano je pozitivno djelovanje BPC-a 157 na cijeljenje kožnih rana i mišićno-tetivnih oštećenja, no nije ispitan njegov utjecaj na prevenciju razvoja incizijskih hernija (IH). Ispitivao se utjecaj BPC-a 157, L-NAME-a i L-arginina na prevenciju razvoja IH-a, veličinu IH-a (VIH), prezentaciju kožnog ožiljka (PKO), trbušne priraslice (TP) i vlačnu čvrstoću rane (VČR) u četiri vremenske točke (7, 14, 21 i 28 dan) na štakorima soja Wistar kod kojih je induciran razvoj IH-a. Sukladno eksperimentalnome protokolu štakorima je kontinuirano davan BPC 157 (0,16 μg/mL ili 0,16 ng/mL, po.), L-NAME (5 mg/kg ip.), L-arginin (100 mg/kg ip.) te njihove kombinacije. BPC 157 smanjio je incidenciju IH-a (p(μg) < 0,0001, p(ng) < 0,0001) kao i VIH-a. Životinje tretirane L-NAME-om i L-argininom imale su veće IH od životinja iz kontrolne skupine. Životinje tretirane BPC-om 157 imale su urednu PKO, kao i manje TP, dok su životinje tretirane L-NAME-om, L-argininom te kombinacijom imale više TP. Životinje tretirane BPC-om 157 tijekom 28 dana imale su veću VČR (p(μg) = 0,0498, p(ng) = 0,0419). BPC 157 pokazao je preventivni učinak na razvoj i veličinu IH-a te pozitivan dugoročni učinak na VČR, što predstavlja potencijal primjene ovoga preparata u prevenciji razvoja IH-a.Positive BPC 157 effect on skin wounds and muscle-tendon is known. Effect on incisional hernia (IH) prevention has not been studied. BPC 157, L-NAME and L-arginineffect on IH development and IH size (IHS), cutaneous wound appearance (CWA), abdominal adhesions (AA) and tensile strength (TS) was monitored for 7, 14, 21, and 28 days on Wistar rats. Ratswere continuously treated with BPC 157 (0,16 μg/mL or 0,16 ng/mL, per os), L-NAME (5 mg/kg ip), L-arginin (100 mg/kg ip) and combinations. BPC 157 reduced the incidence of IH (p(μg) < 0,0001, p(ng) < 0,0001) as well as IHS. Animals treated with L-NAME and L-arginine had larger IHS than control group animals. Animals treated with BPC 157 differed in CWA- predominantly regular healing, as well as less AA, while animals treated with L-NAME, L-arginine and combination had more AA. Animals treated with BPC 157 for 28 days had greater TS (p(μg) = 0,0498, p(ng) = 0,0419). BPC 157 presented preventive effect on IH development, IHS, and long-term positive TS effect. This implies potential usage in IH prevention

A modified open intraperitoneal mesh (Garestin) technique for incisional ventral hernia repair

Background/objective: Incisional hernias (IHs) are a major problem following abdominal surgery. In an effort to resolve large IHs adequately, we herein present our own modified “open intraperitoneal mesh” technique, termed the Garestin technique. Methods: We analyzed early postoperative complications (EPCs; wound infection, hematoma, and seroma) and late postoperative complications (recurrence) in 124 patients operated for IHs and recurrent IHs (RIHs) using our new technique. Our technique involved repairing hernias by preserving the hernia sac, which was later used to conceal the mesh that replaced the abdominal wall defect, thus dividing the mesh from subcutaneous tissue. Results: We operated 66 patients with IH and 58 patients with RIH. In the 4-week postoperative follow-up, 29 patients had EPC; 9 of them had wound infections that healed upon antibiotic therapy, without the need for any surgical procedure. Of the 10 patients with recurrent herniation in the long-term follow-up, 6 previously had EPC. Recurrences occurred 4–25 months after the operation. Conclusion: Our method is reliable and safe for large ventral hernia disposal, but the final conclusion requires a larger number of patients and a longer follow-up period

Esophagogastric anastomosis in rats: improved healing by BPC 157 and L-arginine, aggravated by L-NAME

AIM: To cure typically life-threatening esophagogastric anastomosis in rats, lacking anastomosis healing and sphincter function rescue, in particular. ----- METHODS: Because we assume esophagogastric fistulas represent a particular NO-system disability, we attempt to identify the benefits of anti-ulcer stable gastric pentadecapeptide BPC 157, which was in trials for ulcerative colitis and currently for multiple sclerosis, in rats with esophagocutaneous fistulas. Previously, BPC 157 therapies have promoted the healing of intestinal anastomosis and fistulas, and esophagitis and gastric lesions, along with rescued sphincter function. Additionally, BPC 157 particularly interacts with the NO-system. In the 4 d after esophagogastric anastomosis creation, rats received medication (/kg intraperitoneally once daily: BPC 157 (10 μg, 10 ng), L-NAME (5 mg), or L-arginine (100 mg) alone and/or combined or BPC 157 (10 μg, 10 ng) in drinking water). For rats underwent esophagogastric anastomosis, daily assessment included progressive stomach damage (sum of the longest diameters, mm), esophagitis (scored 0-5), weak anastomosis (mL H2O before leak), low pressure in esophagus at anastomosis and in the pyloric sphincter (cm H2O), progressive weight loss (g) and mortality. Immediate effect assessed blood vessels disappearance (scored 0-5) at the stomach surface immediately after anastomosis creation. ----- RESULTS: BPC 157 (all regimens) fully counteracted the perilous disease course from the very beginning (i.e., with the BPC 157 bath, blood vessels remained present at the gastric surface after anastomosis creation) and eliminated mortality. Additionally, BPC 157 treatment in combination with L-NAME nullified any effect of L-NAME that otherwise intensified the regular course. Consistently, with worsening (with L-NAME administration) and amelioration (with L-arginine), either L-arginine amelioration prevails (attenuated esophageal and gastric lesions) or they counteract each other (L-NAME + L-arginine); with the addition of BPC 157 (L-NAME + L-arginine + BPC 157), there was a marked beneficial effect. BPC 157 treatment for esophagogastric anastomosis, along with NOS-blocker L-NAME and/or NOS substrate L-arginine, demonstrated an innate NO-system disability (as observed with L-arginine effectiveness). BPC 157 distinctively affected corresponding events: worsening (obtained with L-NAME administration that was counteracted); or amelioration (L-arginine + BPC 157-rats correspond to BPC 157-rats). ----- CONCLUSION: Innate NO-system disability for esophagogastric anastomoses, including L-NAME-worsening, suggests that these effects could be corrected by L-arginine and almost completely eliminated by BPC 157 therapy