Investigation of treatment outcomes for severe extremity trauma in an independent orthopedic trauma center: A case series.

BACKGROUND: Severe extremity trauma is one of the most challenging injuries to treat. Limb salvage after severe extremity trauma requires rapid revascularization, accurate and appropriate bone and soft tissue reconstruction, and appropriate management to address critical complications. The purpose of this study was to report the treatment outcomes for severe extremity trauma injuries at our independent orthopedic trauma center. METHODS: This study included patients with severe extremity trauma who underwent major vascular repair or soft tissue reconstruction. Bone reconstruction method, presence or absence of revascularization, and flap type were investigated. Complications were investigated, including revascularization failure, flap failure, infection, and ultimately, whether amputation was required. Additionally, we investigated the number of surgeries performed on each patient at the time of initial hospitalization. RESULTS: Thirty-five patients who underwent revascularization or soft tissue reconstruction were included in this study. Plate fixation was performed in 18 patients, intramedullary nail fixation in 8, screw fixation in 1, pinning in 4, and without implant fixation in 4. Revascularization was performed in six patients, and no vascular complications occurred. Pedicled and free flaps were used in 17 and 16 patients, respectively. Partial flap necrosis occurred in four patients, and arterial occlusion occurred in one. Infection occurred in 10 patients who were treated with frequent irrigation and high-concentration antibiotics local infusion therapy. None of the 35 patients required limb amputation. Mean number of surgeries was 12.5. CONCLUSIONS: The limb of all the 35 patients with severe extremity trauma treated at our independent orthopedic trauma center were salvaged.

Temporary Intravascular Shunting Using a Pruitt-F3 Carotid Shunt for Traumatic Popliteal Artery Injury.

Temporary intravascular shunting (TIVS) is an effective method to shorten the duration of ischemia and contribute to limb salvage in the treatment of popliteal artery injury (PAI). Traditionally used shunt tubes require ligation or clamping to the blood vessel, which has the disadvantage of causing secondary damage to the vessel. We present two cases in which TIVS was performed using the Pruitt-F3 Carotid Shunt (LeMaitre Vascular Inc., Burlington, Mass.) for traumatic PAI and report the effectiveness of the method. Two patients diagnosed with PAI had pallor of the feet and complete motor and sensory paralysis. The patients were immediately transferred to the operating room. PAI was confirmed in one patient by the medial approach and in the other by the posterior approach. In both patients, the vascular injury extended to the vicinity of the bifurcation into the anterior tibial artery. TIVS was performed using a 9Fr Pruitt-F3 Carotid Shunt. In both patients, the color tone of the feet improved. No vascular damage occurred secondary to TIVS. The popliteal artery was reconstructed using a great saphenous vein graft on the contralateral lower extremity, and the limb was salvaged. If the artery is injured near its bifurcation, it may be possible to preserve the branch vessel by using the Pruitt-F3 Carotid Shunt for TIVS.

Mouse Model of Parkinson's Disease with Bilateral Dorsal Striatum Lesion with 6-Hydroxydopamine Exhibits Cognitive Apathy-like Behavior.

Among the symptoms of Parkinson's disease (PD), apathy comprises a set of behavioral, affective, and cognitive features that can be classified into several subtypes. However, the pathophysiology and brain regions that are involved in these different apathy subtypes are still poorly characterized. We examined which subtype of apathy is elicited in a mouse model of PD with 6-hydroxydopamine (6-OHDA) lesions and the behavioral symptoms that are exhibited. Male C57/BL6J mice were allocated to sham (n = 8) and 6-OHDA (n = 13) groups and locally injected with saline or 4 µg 6-OHDA bilaterally in the dorsal striatum. We then conducted motor performance tests and apathy-related behavioral experiments. We then pathologically evaluated tyrosine hydroxylase (TH) immunostaining. The 6-OHDA group exhibited significant impairments in motor function. In the behavioral tests of apathy, significant differences were observed between the sham and 6-OHDA groups in the hole-board test and novelty-suppressed feeding test. The 6-OHDA group exhibited impairments in inanimate novel object preference, whereas social preference was maintained in the three-chamber test. The number of TH+ pixels in the caudate putamen and substantia nigra compacta was significantly reduced in the 6-OHDA group. The present mouse model of PD predominantly showed dorsal striatum dopaminergic neuronal loss and a decrease in novelty seeking as a symptom that is related to the cognitive apathy component.

Efficacy of Orthoplastic Management in the Treatment of Traumatic Popliteal Artery Injury.

Background: Popliteal artery injury (PAI) is a challenging condition. Even with appropriate initial treatment and reconstruction of the associated injuries, extensive soft-tissue necrosis may occur, requiring lower leg amputation. There are no reports on the effectiveness of orthoplastic surgery in treating traumatic PAI. However, orthoplastic surgery is also considered very effective in PAI treatment, which requires delicate handling of soft-tissue and blood vessels. This study aimed to examine the treatment outcomes of traumatic PAI at a trauma center with the capacity for orthoplastic management. Methods: Patients with PAI who were treated at our institution between August 2013 and December 2021 were included in this study. The surgeons included multiple orthoplastic surgeons with capabilities in vascular repair, bone and ligament reconstruction, and soft-tissue reconstruction. Patient demographics, injury characteristics, degree of ischemia, and treatment were investigated. We also investigated whether soft-tissue reconstruction and lower limb amputation were necessary as outcomes of treatment. Results: Fifteen limbs of 14 patients with PAI met the inclusion criteria. Extensive soft-tissue necrosis was observed in three limbs. Two of these limbs were covered with a free latissimus dorsi flap and could be salvaged. In the remaining limb, lower limb amputation was unavoidable because of unexplained cardiac arrest during the initial surgery, but a fillet flap was used to successfully preserve the knee joint. Conclusion: Orthoplastic management has the potential to improve limb salvage rates and provide good outcomes for the treatment of traumatic PAI.

Provisional resection of the nutrient artery in free anterolateral thigh flap debulking surgery.

Fix and flap surgery is the standard treatment for severe open-limb fractures. In cases of complex injuries, secondary surgeries such as additional osteosynthesis, implant removal, bone grafting, and debulking surgery may be required after the soft tissue condition has stabilized. During secondary surgery, if the nutrient vessels of the flap are resected haphazardly and an additional procedure is performed, flap necrosis may occur owing to insufficient blood flow. Creating a hemodynamic system that can withstand secondary surgery through increasing blood flow surrounding the flap is necessary in preventing necrosis. We report a case in which "provisional resection" of the nutrient artery was performed prior to the debulking surgery of a free anterolateral thigh flap. A 45-year-old man sustained an extensive degloving injury on the dorsum of the hand during a car accident. On the fifth day after injury, soft tissue reconstruction with a free anterolateral thigh flap was performed. Although the soft tissue condition was stable, debulking surgery was planned 4 months after the injury because of the thickness of the flap. Flap necrosis may occur if the nutrient artery was resected and debulking surgery was performed simultaneously. Therefore, staged surgery using "provisional resection" of the nutrient artery was selected. First, the nutrient artery was resected. After waiting for 1 week, skin graft removal and flap thinning were performed as the second step. No flap necrosis was observed. "Provisional resection" changes the hemodynamics of the flap to a random pattern due to the delay phenomenon and can prevent flap necrosis caused by secondary surgeries, such as debulking surgery.

Cross-Limb Vascular Shunting for Traumatic Popliteal Artery Injury.

BACKGROUND: Popliteal artery injury (PAI) is a challenging trauma that requires prompt and accurate treatment since the probability of lower-limb amputation increases with the ischemic time. Intravascular shunting and cross-limb vascular shunting (CLS) are used as temporary vascular shunting (TVS) methods to shorten the ischemic time for limb vascular injury. CLS involves sending blood from an artery in a healthy body part to a peripheral vessel in an injured part to immediately resume blood flow to the injured limb. For closed injuries including PAI, CLS may be performed without exploring and identifying the arterial stumps and it enables early reperfusion to the ischemic limb. We report the case series of traumatic PAI treated using CLS and verify the usefulness of CLS. METHODS: All patients with traumatic PAI treated with CLS at our institution between August 2013 and December 2021 were included. Demographic and clinical patient characteristics were extracted from the medical records. Comorbid injuries, severity of acute limb ischemia based on the Rutherford grading scale, time from injury to reperfusion by CLS, time from injury to completion of artery, and the use of fasciotomy were investigated. As outcomes, we investigated the presence or absence of lower extremity amputation during the course of treatment. RESULTS: We used CLS as treatment for 5 cases with traumatic PAI. Based on the Rutherford grading scale for acute limb ischemia, there were one limb with grade 2B and 4 with grade 3. Amputation of the lower extremities was avoided except for 1 extremity in which arterial reconstruction was not achieved due to unexplained cardiac arrest during surgery. CONCLUSIONS: CLS enables early reperfusion of the injured limb and is effective as a TVS method for traumatic PAI with severe ischemia or soft tissue damage.

Surgical delay in reverse sural artery flap prevents congestion of the flap: a case report of the stepwise delay method.

We performed reverse sural artery flap (RSAF) with the stepwise delay method, cutting the vascular pedicle step by step, as the patient had a high risk of flap necrosis. Surgical delay in RSAF is anticipated to prevent not only flap cyanosis but also flap congestion.

Distraction plating for bilaterally severely comminuted distal radius fracture: a case report.

We report a case in which distraction plating was performed for bilateral highly comminuted distal radius fractures. The upper extremities' range of motion and function was acceptable. Thus, distraction plating can be a good option for relatively young patients with severe comminution of the radius and soft tissue damage.

Risk factors for over-telescoping in reverse oblique intertrochanteric fractures.

PURPOSE: Postoperative over-telescoping (OT) with lag screws is often observed in reverse oblique intertrochanteric fractures. This study aimed to clarify the risk factors of OT in patients with reverse oblique intertrochanteric fractures. METHODS: Electronic medical records of patients diagnosed with reverse oblique intertrochanteric fractures using plain radiography who underwent operative fixation with an intramedullary nail between August 2013 and December 2019 were reviewed. Patients were classified into two groups according to the Futamura classification: lateral wall pattern (LW) and reverse oblique pattern (RO). The incidence of OT in the LW and RO groups was compared. Also, we compared the incidence of OT for each reduction type in the LW group. RESULTS: Twenty patients had LW, and nine had RO. OT was observed in eight fractures (42.1%) in the LW group but not in the RO group. The incidence of OT was significantly higher in the LW group than in the RO group (P = 0.0261). Among the 19 fractures with LW, OT was observed in 7 of 10 and 1 of 9 fractures with postoperative reduction in the intramedullary and extramedullary or anatomical types, respectively. In the LW group, the incidence of OT was significantly higher in fractures with postoperative reduction in the intramedullary type than in those of the extramedullary or anatomical type (P = 0.0198). CONCLUSION: Our study showed that the incidence of OT was significantly higher in LW than in RO and that postoperative reduction in the intramedullary type in LW was a risk factor for OT.

GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders.

Substance use disorders (SUDs) are chronic, lifelong disorders that have serious consequences. Repeated substance use alters brain function. G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed widely in the brain, including the reward system, and regulate neuronal excitability. Functional GIRK channels are identified as heterotetramers of GIRK subunits (GIRK1-4). The GIRK1, GIRK2, and GIRK3 subunits are mainly expressed in rodent brain regions, and various addictive substances act on the brain through GIRK channels. Studies with animals (knockout and missense mutation animals) and humans have demonstrated the involvement of GIRK channels in the effects of addictive substances. Additionally, GIRK channel blockers affect behavioral responses to addictive substances. Thus, GIRK channels play a key role in SUDs, and GIRK channel modulators may be candidate medications. Ifenprodil is a GIRK channel blocker that does not have serious side effects. Two clinical trials were conducted to investigate the effects of ifenprodil in patients with alcohol or methamphetamine use disorder. Although the number of participants was relatively low, evidence of its safety and efficacy was found. The present review discusses the potential of GIRK channel modulators as possible medications for addiction. Therapeutic agents that target GIRK channels may be promising for the treatment of SUDs.

Increased production of inflammatory cytokines and activation of microglia in the fetal brain of preeclamptic mice induced by angiotensin II.

Preeclampsia (PE) is a hypertensive obstetric disorder with poor prognosis for both the mother and offspring. Infants born to mothers with PE are known to be at increased risk of developing higher brain dysfunction, such as autism. However, how maternal PE can affect the environment in the fetal brain has not been fully elucidated. Here, we examined the impact of PE on the fetal brain in a mouse model of PE induced by angiotensin II (Ang II), focusing on changes in the inflammatory condition. We confirmed that pregnant mice which were continuously administered Ang II exhibited PE phenotypes, including high blood pressure, proteinuria, and fetal growth restriction. Quantitative RT-PCR analysis demonstrated that the brain of fetuses on embryonic day 17.5 (E17.5) in the Ang II-administered pregnant mice showed increased expression of cytokines, interleukin (IL)- 6, IL-17a, tumor necrosis factor-α, interferon-γ, IL-12, IL-4, and IL-10. Immunohistochemical analysis over a wide area, from the tip of the frontal lobe to the posterior cerebral end, on E17.5 revealed that the microglia in the fetal brain of the Ang II-administered group displayed higher solidity and circularity than those of the control group, indicating that the microglia had transformed to an amoeboid morphology and were activated. Our findings suggest that maternal PE may cause altered inflammatory conditions in the fetal brain, which might be associated with the pathological mechanism connecting maternal PE and brain dysfunction in the offspring.

Early tangential excision debulking after free latissimus dorsi flap reconstruction for soft tissue defects: presentation of three cases.

Bulkiness is patients' major complaint after free latissimus dorsi (LD) flap. We performed tangential excision debulking at 6-13 days following free LD flap in three patients. No flap necrosis or major complications occurred. Tangential excision debulking during the early phase after free LD flap might be safe and reliable.

Interaction between social behavior and paternal age in offspring of the same paternal mice.

AIM: Previous studies reported that advanced paternal age (APA) may increase the risk of autism spectrum disorder (ASD) in offspring. However, effects of APA on behaviors have not been investigated in offspring of the same paternal mice. The present study sought to identify behavioral differences in mouse offspring of the same fathers at different paternal ages. METHODS: We assessed locomotor activity, anxiety-like behavior, and social behavior in male mouse offspring that were born from the same fathers at three different paternal ages (3, 12, and 15 months old). RESULTS: No differences in locomotor activity or anxiety-like behavior were observed among any of the offspring groups. In the three-chamber test, although the control group (3-month-old paternal age) exhibited significantly higher approach behavior toward the novel mouse compared with the novel object, the APA groups (12- and 15-month-old paternal ages) did not exhibit significant approach toward the novel mouse. CONCLUSION: Offspring of 3-month-old fathers but not 12- or 15-month-old APA fathers exhibited social preference behavior. Although the present study was only exploratory, it demonstrated an interaction between social behavior and paternal age in offspring of the same paternal mice.

Increased levels of acidic free-N-glycans, including multi-antennary and fucosylated structures, in the urine of cancer patients.

We recently reported increased levels of urinary free-glycans in some cancer patients. Here, we focused on cancer related alterations in the levels of high molecular weight free-glycans. The rationale for this study was that branching, elongation, fucosylation and sialylation, which lead to increases in the molecular weight of glycans, are known to be up-regulated in cancer. Urine samples from patients with gastric cancer, pancreatic cancer, cholangiocarcinoma and colorectal cancer and normal controls were analyzed. The extracted free-glycans were fluorescently labeled with 2-aminopyridine and analyzed by multi-step liquid chromatography. Comparison of the glycan profiles revealed increased levels of glycans in some cancer patients. Structural analysis of the glycans was carried out by performing chromatography and mass spectrometry together with enzymatic or chemical treatments. To compare glycan levels between samples with high sensitivity and selectivity, simultaneous measurements by reversed-phase liquid chromatography-selected ion monitoring of mass spectrometry were also performed. As a result, three lactose-core glycans and 78 free-N-glycans (one phosphorylated oligomannose-type, four sialylated hybrid-type and 73 bi-, tri- and tetra-antennary complex-type structures) were identified. Among them, glycans with α1,3-fucosylation ((+/- sialyl) Lewis X), triply α2,6-sialylated tri-antennary structures and/or a (Man3)GlcNAc1-core displayed elevated levels in cancer patients. However, simple α2,3-sialylation and α1,6-core-fucosylation did not appear to contribute to the observed increase in the level of glycans. Interestingly, one tri-antennary free-N-glycan that showed remarkable elevation in some cancer patients contained a unique Glcß1-4GlcNAc-core instead of the common GlcNAc2-core at the reducing end. This study provides further insights into free-glycans as potential tumor markers and their processing pathways in cancer.

Pull-in suture: a novel reconstruction technique for tendon avulsion injury at the musculotendinous junction associated with forearm open fracture.

We present three cases of strong one-staged tendon reconstruction for musculotendinous junction avulsion tendon injuries, and called it a 'pull-in suture'. The clinical outcomes of this method are comparable to those of tendon transfer; it is an effective reconstruction method that should be considered as an initial treatment procedure.

Occurrence of a D-arabinose-containing complex-type free-N-glycan in the urine of cancer patients.

Urinary free-glycans are promising markers of disease. In this study, we attempted to identify novel tumor markers by focusing on neutral free-glycans in urine. Free-glycans extracted from the urine of normal subjects and cancer patients with gastric, colorectal, pancreatic and bile duct were fluorescently labeled with 2-aminopyridine. Profiles of these neutral free-glycans constructed using multidimensional high performance liquid chromatography separation were compared between normal controls and cancer patients. The analysis identified one glycan in the urine of cancer patients with a unique structure, which included a pentose residue. To reveal the glycan structure, the linkage fashion, monosaccharide species and enantiomer of the pentose were analyzed by high performance liquid chromatography and mass spectrometry combined with several chemical treatments. The backbone of the glycan was a monoantennary complex-type free-N-glycan containing ß1,4-branch. The pentose residue was attached to the antennal GlcNAc and released by α1,3/4-L-fucosidase. Intriguingly, the pentose residue was consistent with D-arabinose. Collectively, this glycan structure was determined to be Galß1-4(D-Araß1-3)GlcNAcß1-4Manα1-3Manß1-4GlcNAc-PA. Elevation of D-arabinose-containing free-glycans in the urine of cancer patients was confirmed by selected reaction monitoring. This is the first study to unequivocally show the occurrence of a D-arabinose-containing oligosaccharide in human together with its detailed structure.

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) affects reciprocal social interaction and produces abnormal repetitive, restrictive behaviors and interests. The diverse causes of ASD are divided into genetic alterations and environmental risks. The prevalence of ASD has been rising for several decades, which might be related to environmental risks as it is difficult to consider that the prevalence of genetic disorders related to ASD would increase suddenly. The latter includes (1) exposure to medications, such as valproic acid (VPA) and selective serotonin reuptake inhibitors (SSRIs) (2), maternal complications during pregnancy, including infection and hypertensive disorders of pregnancy, and (3) high parental age. Epidemiological studies have indicated a pathogenetic role of prenatal exposure to VPA and maternal inflammation in the development of ASD. VPA is considered to exert its deleterious effects on the fetal brain through several distinct mechanisms, such as alterations of γ-aminobutyric acid signaling, the inhibition of histone deacetylase, the disruption of folic acid metabolism, and the activation of mammalian target of rapamycin. Maternal inflammation that is caused by different stimuli converges on a higher load of proinflammatory cytokines in the fetal brain. Rodent models of maternal exposure to SSRIs generate ASD-like behavior in offspring, but clinical correlations with these preclinical findings are inconclusive. Hypertensive disorders of pregnancy and advanced parental age increase the risk of ASD in humans, but the mechanisms have been poorly investigated in animal models. Evidence of the mechanisms by which environmental factors are related to ASD is discussed, which may contribute to the development of preventive and therapeutic interventions for ASD.

Exposure to GABAA Receptor Antagonist Picrotoxin in Pregnant Mice Causes Autism-Like Behaviors and Aberrant Gene Expression in Offspring.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by impairments in social interaction and restricted/repetitive behaviors. The neurotransmitter γ-aminobutyric acid (GABA) through GABAA receptor signaling in the immature brain plays a key role in the development of neuronal circuits. Excitatory/inhibitory imbalance in the mature brain has been investigated as a pathophysiological mechanism of ASD. However, whether and how disturbances of GABA signaling in embryos that are caused by GABAA receptor inhibitors cause ASD-like pathophysiology are poorly understood. The present study examined whether exposure to the GABAA receptor antagonist picrotoxin causes ASD-like pathophysiology in offspring by conducting behavioral tests from the juvenile period to adulthood and performing gene expression analyses in mature mouse brains. Here, we found that male mice that were prenatally exposed to picrotoxin exhibited a reduction of active interaction time in the social interaction test in both adolescence and adulthood. The gene expression analyses showed that picrotoxin-exposed male mice exhibited a significant increase in the gene expression of odorant receptors. Weighted gene co-expression network analysis showed a strong correlation between social interaction and enrichment of the "odorant binding" pathway gene module. Our findings suggest that exposure to a GABAA receptor inhibitor during the embryonic period induces ASD-like behavior, and impairments in odorant function may contribute to social deficits in offspring.

Ifenprodil for the treatment of methamphetamine use disorder: An exploratory, randomized, double-blind, placebo-controlled trial.

AIM: No effective pharmacological interventions have been developed for patients with methamphetamine use disorder. Ifenprodil is a blocker of G protein-activated inwardly rectifying potassium channels, which play a key role in the mechanism of action of addictive substances. We conducted a randomized, double-blind, exploratory, dose-ranging, placebo-controlled trial to examine the clinical efficacy of ifenprodil for the treatment of methamphetamine use disorder. METHODS: Participants were assigned to three groups: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. The drug administration period was 84 days. The primary outcome was the use or nonuse of methamphetamine during the drug administration period in the placebo group vs 120 mg/d ifenprodil group. We also assessed drug use status, relapse risk based on the Stimulant Relapse Risk Scale (SRRS), drug craving, and methamphetamine in urine as secondary outcomes. We further evaluated drug use status and SRRS subscale scores in patients who were not taking addiction medications during the study. RESULTS: Ifenprodil did not affect the primary or secondary outcomes. However, the additional analyses showed that the number of days of methamphetamine use during the follow-up period and scores on the emotionality problems subscale of the SRRS improved in the 120 mg/d ifenprodil group. The safety of ifenprodil was confirmed in patients with methamphetamine use disorder. CONCLUSION: The present findings did not confirm the efficacy of ifenprodil for methamphetamine use disorder treatment based on the primary or secondary outcomes, but we found evidence of its safety and efficacy in reducing emotionality problems. CLINICAL TRIAL REGISTRATION: The study was registered at the University Hospital Medical Information Network Clinical Trial Registry (no. UMIN000030849) and Japan Registry of Clinical Trials (no. jRCTs031180080). The main registration site is jRCT (https://jrct.niph.go.jp/).

Identification of ß1-3 galactosylglucose-core free-glycans in human urine.

We previously reported the precise structure of acidic free-glycans in human urine. In the present study, structural analysis of neutral free-glycans in urine was performed in fine detail. Urine samples were collected from 21 healthy volunteers and free-glycans extracted from the creatinine-adjusted urine and then fluorescently labeled with 2-aminopyridine. Neutral glycan profiling was achieved by a combination of high-performance liquid chromatography, mass spectrometry, enzymatic digestion, and periodate cleavage. A total of 79 glycans were identified. Because the ABO-blood group antigen containing urinary neutral glycans are major components, profiling patterns were similar between individuals of the same ABO-group. The neutral glycans were composed of lactose-core (Galß1-4Glc) glycans, type-II N-acetyllactosamine-core (GlcNAcß1-4Glc) glycans, hexose oligomers, N-glycans and to our surprise ß1-3 galactosylglucose-core (Galß1-3Glc) glycans. Although glycans with a ß1-3 galactosylglucose-core were identified as major components in urine, comprising structurally simple isomers of a lactose-core, the core structure has not previously been reported. The major ß1-3 galactosylglucose-core glycans were Fucα1-2Galß1-3(Fucα1-4)Glc, GalNAcα1-3(Fucα1-2)Galß1-3(Fucα1-4)Glc and Galα1-3(Fucα1-2)Galß1-3(Fucα1-4)Glc, corresponding to H-, A-, and B-blood group antigens, respectively. Three lactosamine extended ß1-3 galactosylglucose-core glycans were also detected as minor components. Elucidating the biosynthesis of ß1-3 galactosylglucose will be crucial for understanding the in vivo function of these glycans.