The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport.

Cilia are important cellular organelles for signaling and motility and are constructed via intraflagellar transport (IFT). RabL2 is a small GTPase that localizes to the basal body of cilia via an interaction with the centriolar protein CEP19 before downstream association with the IFT machinery, which is followed by initiation of IFT. We reconstituted and purified RabL2 with CEP19 or IFT proteins to show that a reconstituted pentameric IFT complex containing IFT81/74 enhances the GTP hydrolysis rate of RabL2. The binding site on IFT81/74 that promotes GTP hydrolysis in RabL2 was mapped to a 70-amino-acid-long coiled-coil region of IFT81/74. We present structural models for RabL2-containing IFT complexes that we validate in vitro and in cellulo and demonstrate that Chlamydomonas IFT81/74 enhances GTP hydrolysis of human RabL2, suggesting an ancient evolutionarily conserved activity. Our results provide an architectural understanding of how RabL2 is incorporated into the IFT complex and a molecular rationale for why RabL2 dissociates from anterograde IFT trains soon after departure from the ciliary base.

Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer's disease.

Adiponectin (APN) is an adipokine which predominantly expresses in adipocytes with neuroprotective and anti-inflammatory effects. We have recently indicated that circulatory trimeric APN can enter the brain by crossing the blood-brain barrier (BBB) and modulate microglia-mediated neuroinflammation. Here, we found that the microglial NLR family pyrin domain containing 3 (NLRP3)-inflammasome activation was exacerbated in APN-/-5xFAD mice in age-dependent manner. The focus of this study was to develop a new and tractable therapeutic approach for treating Alzheimer's disease (AD)-related pathology in 5xFAD mice using peripheral APN gene therapy. We have generated and transduced adeno-associated virus (AAV2/8) expressing the mouse mutated APN gene (APNC39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APNTri). Single dose of AAV2/8-APNC39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APNTri was able to cross the BBB. Overexpression of APNTri decreased both the soluble and fibrillar Aß in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aß-induced IL-1ß and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APNTri-treated 5xFAD mice with reduction of dystrophic neurites. These findings demonstrate that peripheral gene delivery to overexpress trimeric APN can be a potential therapy for AD.

Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer's disease mouse model.

Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN-/-) mice developed Alzheimer's like pathologies, cerebral insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased Aß-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated insulin activities or cerebral insulin resistance contributes to neuroinflammation and Alzheimer's disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN-/- mice to generate APN-deficient 5xFAD (5xFAD;APN-/-). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood-brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN-/- mice. AdipoRon lowered plaque and Aß levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward Aß was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.

Adiponectin suppresses amyloid-ß oligomer (AßO)-induced inflammatory response of microglia via AdipoR1-AMPK-NF-κB signaling pathway.

BACKGROUND: Microglia-mediated neuroinflammation is important in Alzheimer's disease (AD) pathogenesis. Extracellular deposition of ß-amyloid (Aß), a major pathological hallmark of AD, can induce microglia activation. Adiponectin (APN), an adipocyte-derived adipokine, exerts anti-inflammatory effects in the periphery and brain. Chronic APN deficiency leads to cognitive impairment and AD-like pathologies in aged mice. Here, we aim to study the role of APN in regulating microglia-mediated neuroinflammation in AD. METHODS: Inflammatory response of cultured microglia (BV2 cells) to AßO and effects of APN were studied by measuring levels of proinflammatory cytokines (tumor necrosis factor α [TNFα] and interleukin-1ß [IL-1ß]) in cultured medium before and after exposure to AßO, with and without APN pretreatment. Adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2) were targeted by small interference RNA. To study the neuroprotective effect of APN, cultured HT-22 hippocampal cells were treated with conditioned medium of AßO-exposed BV2 cells or were co-cultured with BV2 cells in transwells. The cytotoxicity of HT-22 hippocampal cells was assessed by MTT reduction. We generated APN-deficient AD mice (APN-/-5xFAD) by crossing APN-knockout mice with 5xFAD mice to determine the effects of APN deficiency on microglia-mediated neuroinflammation in AD. RESULTS: AdipoR1 and AdipoR2 were expressed in BV2 cells and microglia of mice. Pretreatment with APN for 2 h suppressed TNFα and IL-1ß release induced by AßO in BV2 cells. Additionally, APN rescued the decrease of AMPK phosphorylation and suppressed nuclear translocation of nuclear factor kappa B (NF-κB) induced by AßO. Compound C, an inhibitor of AMPK, abolished these effects of APN. Knockdown of AdipoR1, but not AdipoR2 in BV2 cells, inhibited the ability of APN to suppress proinflammatory cytokine release induced by AßO. Moreover, pretreatment with APN inhibited the cytotoxicity of HT-22 cells co-cultured with AßO-exposed BV2 cells. Lastly, APN deficiency exacerbated microglia activation in 9-month-old APN-/-5xFAD mice associated with upregulation of TNFα and IL-1ß in the cortex and hippocampus. CONCLUSIONS: Our findings demonstrate that APN inhibits inflammatory response of microglia to AßO via AdipoR1-AMPK-NF-κB signaling, and APN deficiency aggravates microglia activation and neuroinflammation in AD mice. APN may be a novel therapeutic agent for inhibiting neuroinflammation in AD.

Surgery for urinary incontinence in women: Report from the 6th international consultation on incontinence.

Urinary incontinence is a prevalent condition worldwide and causes a tremendous impact on a woman's quality of life. While conservative and non-surgical therapies are options for treatment, surgery for stress urinary incontinence (SUI) is common. Options include colposuspension, slings (pubovaginal and midurethral), and periurethral bulking. While evidence supports each of these options in the treatment of SUI, each is associated with various rates of success and unique adverse event profiles. Urgency urinary incontinence (UUI) is initially treated with behavioral modification and pharmacologic means, with surgery reserved for those with refractory symptoms or significant complications from medication use. At present, intravesical onabotulinumtoxinA injections, percutaneous tibial nerve stimulation, and sacral neurostimulation are all viable options for refractory UUI/overactive bladder. As with surgical interventions for SUI, each of these is, likewise, associated with unique outcomes and adverse event profiles. Herein, we summarize the findings and conclusions from the 6th International Consultation on Incontinence (ICI) regarding surgical treatment of urinary incontinence in women.

One-pot synthesis of carbon dots using two different acids and their respective unique photoluminescence property.

Carbon dots, a new class of nanomaterial with unique optical property and have great potential in various applications. This work demonstrated the possibility of tuning the emission wavelength of carbon dots by simply changing the acid type used during synthesis. In particular, sulfuric and phosphoric acids and a mixture of the two were used to carbonize the same starting precursor, sucrose. This resulted in the isolation of carbon dots with blue (440 nm) and green (515 nm) emission. Interestingly, the use of an acid mixture at various ratios did not shift the initial emission profile, but did obviously alter the fluorescence efficiency of the peaks. This clearly showed that acid type can be used as an alternative tool to produce carbon dots that have different emissions using the same starting precursor. Copyright © 2016 John Wiley & Sons, Ltd.

Potential Neuroprotective Effects of Adiponectin in Alzheimer's Disease.

The adipocyte-secreted protein adiponectin (APN) has several protective functions in the peripheral tissues including insulin sensitizing, anti-inflammatory and anti-oxidative effects that may benefit neurodegenerative diseases such as Alzheimer's disease (AD). In addition, dysregulation of cerebral insulin sensitivities and signaling activities have been implicated in AD. Emerging insights into the mechanistic roles of adiponectin and AD highlight the potential therapeutic effects for AD through insulin signaling.

A first reported case of clear cell carcinoma associated with delayed extrusion of midurethral tape.

We present the first reported case of clear cell carcinoma associated with a midurethral tape (MUT), the possible hypotheses and the management pitfalls we encountered. We report a 58-year-old woman who presented with symptoms of urinary tract infection and acute retention of urine associated with vaginal tape exposure 10 years after placement of an inside-out transobturator tape. She subsequently had a partial transobturator tape excision and a diagnostic cystoscopy, which revealed inflammatory changes within the urethra. Postoperatively, her symptoms persisted and the vaginal epithelium healed poorly. A biopsy of the friable tissue reported clear cell carcinoma. Imaging showed a locally invasive periurethral mass and bony and lymphatic metastases. This was treated with palliative radiation therapy. She was still receiving palliative care 5 months after the initial surgery.

Association of dietary inflammation with tooth loss and cognitive decline in older adults from cross-sectional data: The moderated role of albumin.

OBJECTIVE: Growing evidence suggests a potential connection between tooth loss and cognitive function in recent years. Increasing studies have focused on their inter-relationship, however, the underlying mechanism has yet to be fully elucidated. Few studies have considered the role of dietary inflammation and serum albumin in the association between tooth loss and cognitive function. Therefore, the aim of this study was to explore the role of dietary inflammation and serum albumin in the association between tooth loss and cognitive impairment. METHODS: A sample of 1,009 US adults from the National Health and Nutrition Examination Survey (NHANES) provided data on oral condition, cognitive function, dietary intake, and serum tests. The association between tooth loss (exposure variable) and cognitive function (outcome variable) was assessed by linear regression. Furthermore, a moderated mediation model was established to examine the influence of dietary inflammation on the association between tooth loss and cognitive tests, and the visualization of the moderating effect of serum albumin concentration was displayed through the Johnson-Neyman curve. RESULTS: Participants with impaired dentition had worse cognitive function and a higher Dietary Inflammation Index (DII). DII was highly correlated with Immediate Recall Test (IR), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST), which mediated 16.46 %, 14.41 % and 11.28 % of the effect between tooth loss and cognitive functions. Additionally, the relationship between DII and DSST was moderated by serum albumin concentration. CONCLUSION: Tooth loss was associated with cognitive function which was affected by pro-inflammatory dietary patterns and serum albumin level. CLINICAL SIGNIFICANCE: This study presents evidence for dentists that dietary pattern change due to tooth loss plays a role in cognitive deterioration, which can also be moderated by serum albumin level. Therefore, the preservation of natural teeth is important for cognitive function, especially in an immunocompromised population with decreased serum albumin concentrations.

Myristoylated Neuronal Calcium Sensor-1 captures the ciliary vesicle at distal appendages.

The primary cilium is a microtubule-based organelle that cycles through assembly and disassembly. In many cell types, formation of the cilium is initiated by recruitment of ciliary vesicles to the distal appendage of the mother centriole. However, the distal appendage mechanism that directly captures ciliary vesicles is yet to be identified. In an accompanying paper, we show that the distal appendage protein, CEP89, is important for thef ciliary vesicle recruitment, but not for other steps of cilium formation (Tomoharu Kanie, Love, Fisher, Gustavsson, & Jackson, 2023). The lack of a membrane binding motif in CEP89 suggests that it may indirectly recruit ciliary vesicles via another binding partner. Here, we identify Neuronal Calcium Sensor-1 (NCS1) as a stoichiometric interactor of CEP89. NCS1 localizes to the position between CEP89 and a ciliary vesicle marker, RAB34, at the distal appendage. This localization was completely abolished in CEP89 knockouts, suggesting that CEP89 recruits NCS1 to the distal appendage. Similarly to CEP89 knockouts, ciliary vesicle recruitment as well as subsequent cilium formation was perturbed in NCS1 knockout cells. The ability of NCS1 to recruit the ciliary vesicle is dependent on its myristoylation motif and NCS1 knockout cells expressing myristoylation defective mutant failed to rescue the vesicle recruitment defect despite localizing proper localization to the centriole. In sum, our analysis reveals the first known mechanism for how the distal appendage recruits the ciliary vesicles.

Identification of a novel adiponectin receptor and opioid receptor dual acting agonist as a potential treatment for diabetic neuropathy.

Diabetic neuropathy (DN) is a long-term complication of diabetes mellitus, affecting different periphery nerve systems including sensory and motor neurons. Hyperglycemia is the major cause of DN with symptoms such as weakness of balance or coordination, insensitivity to sensation, weakness of the muscles as well as numbness and pain in limbs Analgesic drug such as opioids can be effective to relief neuropathy pain but there is no effective treatment. Adiponectin is an anti-diabetic adipokine, which possesses insulin-sensitizing and neuroprotective effects. In this project, we aim to identify an agent which is dual acting to opioid and adiponectin receptors. Within a virtual screening repositioning campaign, a large collection of compounds with different structures comprehensive of adipoRon-like piperidine derivatives was screened by docking. Recently developed opioid receptor benzomorphanic agonists finally emerged as good ligands to adiponectin receptors showing some 2D and 3D structural similarities with AdipoRon. Particularly, we have identified (+)-MML1017, which has high affinity to the same binding domain of AdipoR1 and AdipoR2 as AdipoRon. Our western blot results indicate (+)-MML1017 activates AMPK phosphorylation through both adipoR1 and adipoR2 in neuronal cell line. Moreover, pretreatment of (+)-MML1017 can improve the cell viability with motor neurons under hyperglycermic conditions. The (+)-MML1017 also activates µ-opioid receptor cells in a concentration-dependent manner. Our study identified a novel compound having dual activity on opioid receptors and adiponectin receptors that may have analgesic effects and neuroprotective effects to treat diabetic neuropathy.

Fe65-engineered neuronal exosomes encapsulating corynoxine-B ameliorate cognition and pathology of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the predominant impairment of neurons in the hippocampus and the formation of amyloid plaques, hyperphosphorylated tau protein, and neurofibrillary tangles in the brain. The overexpression of amyloid-ß precursor protein (APP) in an AD brain results in the binding of APP intracellular domain (AICD) to Fe65 protein via the C-terminal Fe65-PTB2 interaction, which then triggers the secretion of amyloid-ß and the consequent pathogenesis of AD. Apparently, targeting the interaction between APP and Fe65 can offer a promising therapeutic approach for AD. Recently, exosome, a type of extracellular vesicle with diameter around 30-200 nm, has gained much attention as a potential delivery tool for brain diseases, including AD, due to their ability to cross the blood-brain barrier, their efficient uptake by autologous cells, and their ability to be surface-modified with target-specific receptor ligands. Here, the engineering of hippocampus neuron cell-derived exosomes to overexpress Fe65, enabled the development of a novel exosome-based targeted drug delivery system, which carried Corynoxine-B (Cory-B, an autophagy inducer) to the APP overexpressed-neuron cells in the brain of AD mice. The Fe65-engineered HT22 hippocampus neuron cell-derived exosomes (Fe65-EXO) loaded with Cory-B (Fe65-EXO-Cory-B) hijacked the signaling and blocked the natural interaction between Fe65 and APP, enabling APP-targeted delivery of Cory-B. Notably, Fe65-EXO-Cory-B induced autophagy in APP-expressing neuronal cells, leading to amelioration of the cognitive decline and pathogenesis in AD mice, demonstrating the potential of Fe65-EXO-Cory-B as an effective therapeutic intervention for AD.

Uterine prolapse complicating pregnancy and labor: a case report and literature review.

BACKGROUND: Uterine and cervical prolapse is a rare occurrence in pregnancy. It can be associated with minor cervical desiccation and ulceration to devastating maternal fatalities. The scope of complications includes urinary retention, preterm labor, premature delivery, fetal demise, maternal sepsis, and urinary retention. METHODS: We present a case of a lady, who developed uterine and cervical prolapse during pregnancy and the issues surrounding her antenatal and intrapartum management. RESULTS AND CONCLUSION: This case report highlights the effectiveness of a Gellhorn pessary for uterine prolapse in pregnancy.

Integrated media presentation in multidisciplinary head and neck oncology meetings.

Multidisciplinary meetings (MDMs) are an essential part of the management of head and neck cancer. Practice care guidance set up by the British Association of Head and Neck Oncologists has recommended that MDMs should have appropriate projection equipment for computer-generated images so that all members of group have access to the same information. The aim of this paper is to review our experience with the integrated visual presentation of head and neck oncology patients and to demonstrate its advantages over conventional approaches. Digital photographs are taken of patients and of their index tumour at presentation or at the time of diagnostic endoscopy. All relevant pre-treatment digitised images from tumour sites and radiological images and histological slides are incorporated into a single presentation using Microsoft PowerPoint software. During the past 2 years, on-line radiological scans have also become accessible for the meeting to aid treatment planning. Subsequently, all peri-operative pictures and post-surgical macroscopic and microscopic histopathological images are added to each patient's presentation, which is then hyperlinked into the agenda. The Guy's and St Thomas' Head and Neck Cancer Centre treats over 400 patients a year, and since 2002, all new cancer diagnoses have been discussed in the weekly MDM as described above. A total of 1,638 presentations have been incorporated in a centralized database that is updated in the event of recurrence, further primary tumours or other clinical developments. Satisfactory documentation and staging of head and neck tumours must include a verbal description, accurate measurement, diagrammatic representation, photographic recording and appropriate radiological imaging. Integrated presentation at MDM collates all relevant findings for clinical management decisions on patients with head and neck cancer. This approach is also an extremely valuable adjunct to long-term clinical monitoring.

Conditional deletion of platelet derived growth factor receptor alpha (Pdgfra) in urorectal mesenchyme causes mesenchyme apoptosis and urorectal developmental anomalies in mice.

In mammals, urorectal development starts at early embryonic stage, defective urorectal development results in anorectal malformations, which are common congenital developmental defects of the anus and the urethra in newborns. The etiology and embryology of the defects are still largely unknown. Platelet-derived growth factor receptor alpha (Pdgfra) is a cell surface receptor tyrosine kinase, upon binding to its ligands (Pdgfa-d), mediates intracellular signaling and regulates embryonic development. The expression of Pdgfra is tightly regulated in the developing urorectal mesenchyme, and its dysregulation is associated with urorectal defects in animals with urorectal defects. Knockout of Pdgfra induces early embryo lethality which precludes investigation of Pdgfra in urorectal development. To address the temporal requirement of Pdgfra in urorectal development, we conditionally deleted Pdgfra in Pdgfra-expressing tissues using a tamoxifen inducible Cre-loxP approach in mice, examined the urorectal development in Pdgfra conditional knockout (Pdgfra-cKO) embryos. We showed that conditional deletion of Pdgfra in Pdgfra-expressing tissues at E10-E11 caused cloaca septation defect, anteriorly displaced anus, defective urogenital folds development and abnormal urethra tubularization in both male and female mice. Furthermore, we showed that Pdgfra was required for the survival of urorectal mesenchyme, deletion of Pdgfra caused apoptosis in the peri-cloacal, the peri-urethra and the urorectal septum mesenchyme of Pdgfra-cKO mutants, associated with an induction of p53, Ndrg1 and activation of caspase-3 in Pdgfra-cKO embryos. In conclusion, Pdgfra is required for the development and survival of the urorectal mesenchyme in embryo, dysregulated Pdgfra signaling induced urorectal defects in mice resembling human congenital diseases of anorectal malformations and hypospadias. Perturbation of PDGFRA signaling may contribute to anorectal malformations and hypospadias in human.

Aquaporin-4 Autoantibodies From Neuromyelitis Optica Spectrum Disorder Patients Induce Complement-Independent Immunopathologies in Mice.

Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system inflammatory disorders causing significant morbidities and mortality. The majority of NMOSD patients have autoimmunity against aquaporin-4 (AQP4), evidenced by seropositivity for autoantibodies against aquaporin-4 (AQP4-IgG). AQP4-IgG is pathogenic with neuroinflammation initiated upon binding of AQP4-IgG to astrocytic AQP4. Complement activation contributes to astrocytic cytotoxicity, neuroinflammation, and tissue necrosis in NMOSD, but the role of complement-independent mechanisms is uncertain. We studied the complement-independent pathogenic effects of AQP4-IgG by passive transfer of IgG from NMOSD patients to mice with breached blood-brain barrier (BBB). Mice, pretreated with bacterial proteins, received daily intraperitoneal injections of IgG purified from AQP4-IgG-seropositive NMOSD patients [IgG(AQP4+)], or IgG from AQP4-IgG-seronegative patients [IgG(AQP4-)] or healthy subjects [IgG(Healthy)] for 8 days. Motor function was tested by walking across narrow beams, and spinal cords were collected for immunofluorescent analysis. We found that human IgG infiltrated into cord parenchyma of mice with breached BBB without deposition of complement activation products. Spinal cord of mice that received IgG(AQP4+) demonstrated loss of AQP4 and glial fibrillary acidic protein (suggestive of astrocyte loss), decrease in excitatory amino acid transporter 2, microglial/macrophage activation, neutrophil infiltration, patchy demyelination, and loss in axonal integrity. Mice that received IgG(AQP4+) required longer time with more paw slips to walk across narrow beams indicative of motor slowing and incoordination. Our findings suggest that AQP4-IgG induces complement-independent cord pathologies, including astrocytopathy, neuroinflammation, demyelination, and axonal injuries/loss, which are associated with subtle motor impairments. These complement-independent pathophysiologies likely contribute to early NMOSD lesion development.

Chronic adiponectin deficiency leads to Alzheimer's disease-like cognitive impairments and pathologies through AMPK inactivation and cerebral insulin resistance in aged mice.

BACKGROUND: Insulin resistance is the major pathogenesis underlying type 2 diabetes mellitus (T2DM) and these patients have doubled risk of Alzheimer's disease (AD). Increasing evidence suggests that insulin resistance plays an important role in AD pathogenesis, possibly due to abnormal GSK3ß activation, causing intra- and extracellular amyloid-beta (Aß) accumulation. Adiponectin (APN) is an adipokine with insulin-sensitizing and anti-inflammatory effects. Reduced circulatory APN level is associated with insulin resistance and T2DM. The role of APN in AD has not been elucidated. In this study, we aim to examine if adiponectin deficiency would lead to cerebral insulin resistance, cognitive decline and Alzheimer's-like pathology in mice. METHODS: To study the role of adiponectin in cognitive functions, we employed adiponectin-knockout (APN-KO) mice and demonstrated chronic APN deficiency in their CNS. Behavioral tests were performed to study the cognitions of male APN-KO mice. Brains and tissue lysates were collected to study the pathophysiological and molecular changes in the brain of APN-KO mice. SH-SY5Y neuroblastoma cell line was used to study the molecular mechanism upon APN and insulin treatment. RESULTS: Aged APN-deficient mice displayed spatial memory and learning impairments, fear-conditioned memory deficit as well as anxiety. These mice also developed AD pathologies including increased cerebral Aß42 level, Aß deposition, hyperphosphorylated Tau proteins, microgliosis and astrogliosis with increased cerebral IL-1ß and TNFα levels that associated with increased neuronal apoptosis and reduced synaptic proteins levels, suggesting APN deficiency may lead to neuronal and synaptic loss in the brain. AD pathologies-associated APN-KO mice displayed attenuated AMPK phosphorylation and impaired insulin signaling including decreased Akt induction and increased GSK3ß activation in the hippocampus and frontal cortex. Aged APN-KO mice developed hippocampal insulin resistance with reduced pAkt induction upon intracerebral insulin injection. Consistently, APN treatment in SH-SY5Y cells with insulin resistance and overexpressing Aß induce higher pAkt levels through AdipoR1 upon insulin treatment whereas the induction was blocked by compound C, indicating APN can enhance neuronal insulin sensitivity through AMPK activation. CONCLUSION: Our results indicated that chronic APN deficiency inactivated AMPK causing insulin desensitization and elicited AD-like pathogenesis in aged mice which also developed significant cognitive impairments and psychiatric symptoms.

Technical variations of the bipedicled TRAM flap in unilateral breast reconstruction: effects of conventional versus microsurgical techniques of pedicle transfer on complications rates.

In cases of unilateral breast reconstruction with a transverse rectus abdominis musculocutaneous (TRAM) flap, poorly perfused tissue, which is normally excised to avoid subsequent fat necrosis, must sometimes be used to achieve adequate breast size and projection. In such cases, incorporation of a second vascular pedicle into the flap design improves perfusion. The authors retrospectively examined their experience with bipedicled TRAM flap-based unilateral breast reconstruction to determine whether the use of microsurgical rather than conventional (nonmicrosurgical) techniques for flap transfer resulted in lower incidences of flap-site fat necrosis and donor-site hernia/bulge. The authors retrospectively reviewed the medical records of all patients who underwent unilateral breast reconstruction with a bipedicled TRAM or deep inferior epigastric perforator flap between January of 1991 and March of 2001. Group 1 consisted of patients who had undergone flap transfer using a conventional technique for both pedicles; group 2, patients who had flap transfer using a conventional technique for one pedicle and a microsurgical technique for the other; and group 3, patients who had flap transfer using a microsurgical technique for both pedicles. Of the 863 patients identified, 72 (8.3 percent) had undergone reconstruction using a bipedicled flap. There were 43 patients in group 1, 24 patients in group 2, and five patients in group 3. Only one case of total flap loss had occurred (group 1). Partial flap loss occurred in two patients in group 1 (5 percent) and three patients in group 2 (13 percent). Fat necrosis occurred more frequently in groups 1 (23 percent) and 2 (29 percent) than in group 3 (0 percent) (p = 0.5, Fisher's exact test). Similarly, bulge or hernia was more common in groups 1 (12 percent) and 2 (4 percent) than in group 3 (0 percent) (p = 0.6, Fisher's exact test). In this study, patients who received a bipedicled TRAM flap using microsurgical techniques alone (group 3) appeared to have better flap perfusion and less frequent hernia/bulge than did patients who underwent flap transfer using conventional (group 1) or combined techniques (group 2). However, these differences were not statistically significant, and this trend must be verified in a larger study.

Optimizing autologous breast reconstruction in thin patients.

Breast reconstruction with a transverse rectus abdominis myocutaneous (TRAM) flap plus an implant has been proposed as an option for women with a thin body habitus who do not have sufficient abdominal tissue to permit reconstruction with a TRAM flap alone. The standard autologous tissue reconstructive procedure in these women is a combined latissimus dorsi myocutaneous flap and breast implant. We reviewed our experience performing TRAM flap/implant and latissimus dorsi flap/implant breast reconstruction to compare complication rates and aesthetic outcomes between these two types of reconstruction. Between 1992 and 1999, 88 breasts were reconstructed at our institution using an autologous tissue flap combined with a breast implant (44 with a TRAM flap/implant and 44 with a latissimus dorsi flap/implant). Recipient-site and donor-site complications for the two procedures were compared using Fisher's exact test; a panel of unbiased, blinded judges compared the aesthetic outcomes. The recipient-site complication rate was lower for the TRAM flap/implant group than for the latissimus dorsi flap/implant group (18 percent versus 34 percent, p = 0.09). Most recipient-site complications in the TRAM flap/implant group were related to fluid collection around the implant. In the TRAM flap/implant group, complications occurred in 37 percent of the reconstructions that had immediate implant placement and in none of the reconstructions with delayed implant placement (p = 0.01). In the TRAM flap/implant reconstructions with immediate implant placement, the recipient-site complication rate was 50 percent when implants were completely filled with saline, but no complications occurred with incompletely filled, postoperatively adjustable implants (p = 0.03). No microvascular complications occurred with immediate placement of breast implants under TRAM flaps. Donor-site complications included a hematoma, a seroma, and an umbilical necrosis in the TRAM flap/implant group and six cases of seroma formation in the latissimus dorsi flap/implant group. The comparison of aesthetic outcome was statistically significant for the TRAM flap/implant group, which had a higher overall mean score than the latissimus dorsi flap/implant group did (3.29 versus 2.85, p = 0.01). The results of this study suggest that the TRAM flap/implant breast reconstruction should be considered as an alternative to the latissimus dorsi flap/implant breast reconstruction in women with a thin body habitus.

Pelvi-perineal flap reconstruction: normal imaging appearances and post-operative complications on cross-sectional imaging.

Radical pelvic surgery is often required in patients with advanced, persistent or recurrent gynaecological and anorectal malignancies. In the last decade, pedicled flap reconstructions have been increasingly used for pelvic floor and neovaginal reconstruction, introducing well-vascularised non-irradiated tissue into the wound cavity and hence reducing wound complications. The aim of this pictorial review is to describe the normal post-operative cross-sectional imaging appearances of the most commonly used pelvi-perineal flap reconstructions and to illustrate the complications that may arise at the flap donor and recipient sites.