Pancreatic Islet Vasculature Adapts to Insulin Resistance Through Dilation and Not Angiogenesis

Pancreatic islets adapt to insulin resistance through a complex set of changes, including β-cell hyperplasia and hypertrophy. To determine if islet vascularization changes in response to insulin resistance, we investigated three independent models of insulin resistance: ob/ob, GLUT4^+/−, and mice with high-fat diet–induced obesity. Intravital blood vessel labeling and immunocytochemistry revealed a vascular plasticity in which islet vessel area was significantly increased, but intraislet vessel density was decreased as the result of insulin resistance. These vascular changes were independent of islet size and were only observed within the β-cell core but not in the islet periphery. Intraislet endothelial cell fenestration, proliferation, and islet angiogenic factor/receptor expression were unchanged in insulin-resistant compared with control mice, indicating that islet capillary expansion is mediated by dilation of preexisting vessels and not by angiogenesis. We propose that the islet capillary dilation is modulated by endothelial nitric oxide synthase via complementary signals derived from β-cells, parasympathetic nerves, and increased islet blood flow. These compensatory changes in islet vascularization may influence whether β-cells can adequately respond to insulin resistance and prevent the development of diabetes.Pancreatic islets are highly vascularized, and this feature is critical for β-cells to rapidly sense the blood glucose and secrete insulin into the systemic circulation (1,2). Islet vascularization begins early in pancreas development and is maintained in adulthood as a consequence of islet cell production of angiogenic factors such as vascular endothelial growth factor-A (VEGF-A) and angiopoietin-1 (Ang-1) (3–6). These factors recruit endothelial cells (ECs), stimulate blood vessel growth and maturation, and in the case of VEGF-A, promote formation of EC fenestrations (5,6). In addition, ECs adjacent to pancreatic epithelium reciprocally influence islet cell differentiation and development (7,8).β-Cells have a remarkable ability to respond to changes in an organism’s metabolic state, such as changes in the blood glucose or increased insulin requirements. For example, when insulin resistance develops, β-cells of the pancreatic islet can dramatically increase insulin production and secretion with an increase of β-cell mass, thus maintaining normoglycemia (9,10). In this way, mouse models with marked insulin resistance and humans with obesity-related insulin resistance are hyperinsulinemic but not hyperglycemic. The mechanisms underlying this β-cell adaptation to insulin resistance and their subsequent failure in some individuals who develop type 2 diabetes are incompletely understood.Because of the highly vascularized state of pancreatic islets and the marked changes in β-cell size and number in the setting of insulin resistance, we hypothesized that the islet vasculature must adapt to these changes in β-cell mass and insulin requirements. We envisioned that a hyperplastic islet, like a growing tumor mass, would increase production of angiogenic factors to increase its vascular supply with expanding β-cell mass (11). To test this hypothesis, we examined islet vascularization in three mouse models of insulin resistance and found, unexpectedly, that islet vessel density was decreased, not increased, and that the intraislet vasculature became markedly dilated whereas vessels in the exocrine tissue were unchanged. The dilation of intraislet capillaries was independent of islet size, suggesting the vascular adaptation may primarily support increased β-cell insulin secretory demand rather than β-cell mass expansion. Moreover, these vascular changes were accompanied by an increase in islet parasympathetic innervation. Our results indicate that the metabolic state influences islet angioarchitecture and innervation, suggesting that islet neurovascular remodeling may influence whether β-cells can adequately respond to insulin resistance and maintain normoglycemia.     

Neurophysiologic Monitoring Can Predict Iatrogenic Injury During Acetabular and Pelvic Fracture Fixation

Background:

Nerve injury during acetabular and pelvic fracture fixation can have devastating consequences for trauma patients already in a compromised situation.

Questions/Purposes:

This study aims to evaluate the efficacy of multimodality intraoperative neurophysiologic monitoring during acetabular and pelvic fracture fixation in identifying emerging iatrogenic nerve injury.

Methods:

Sixty patients were retrospectively identified after surgical fixation following acetabular or pelvic fracture. Neuromonitoring during surgery was performed using three different modalities, transcranial electric motor evoked potential (tceMEP), somatosensory evoked potential (SSEP), and electromyographic (EMG) monitoring. Each modality was evaluated for sensitivity and specificity of detecting an intraoperative nerve injury.

Results:

tceMEP monitoring was found to be 100% sensitive and 86% specific at detecting an impending nerve injury. The sensitivity and specificity of SSEP were 75% and 94%, while EMG sensitivity was unacceptably low at 20% although specificity was 93%.

Conclusions:

Multimodality neuromonitoring of transcranial electric motor and peroneal nerve somatosensory evoked potentials with or without spontaneous EMG monitoring is a safe and effective method for detecting impending nerve injury during acetabular and pelvic surgery.     

Time-dependent cognitive deficits associated with first and second generation antipsychotics: cholinergic dysregulation as a potential mechanism

Although cognitive dysfunction is considered one of the more debilitating symptoms of schizophrenia, there is a fundamental gap in our knowledge of how the primary pharmacologic treatments of this disease, first- and second-generation antipsychotics (FGAs and SGAs, respectively), affect cognition, particularly over extended periods of time. Moreover, it has been known for decades that chronic treatment with FGAs can lead to imbalances in cholinergic function in the striatum that result in movement disorders; however, there is a growing body of evidence to suggest that both FGAs and SGAs can lead to cholinergic alterations in brain areas more traditionally considered as memory-related, such as cortical and hippocampal regions. Data from our laboratories in rodents indicate that some SGAs (if administered for sufficient periods of time) can be associated with impairments in memory-related task performance as well as alterations in the cholinergic enzyme choline acetyltransferase, the vesicular acetylcholine transporter, and nicotinic (alpha(7)) and muscarinic (M(2)) acetylcholine receptors. Given the well documented importance of central cholinergic function to information processing and cognitive function, it is important that the mechanisms for such chronic antipsychotic effects be identified. In this review, two potential mechanisms for long-term antipsychotic-related cholinergic alterations in the central nervous system are discussed: 1) antipsychotic antagonist activity at dopaminergic-D(2) receptors on cholinergic neurons and 2) antipsychotic effects on neurotrophins that support cholinergic neurons, such as nerve growth factor and brain derived growth factor. Novel strategies to optimize the therapeutics of schizophrenia and maintain cognitive function via adjunctive cholinergic compounds and antipsychotic crossover approaches are also discussed.     

Osseointegrated implants in craniofacial application: current status

The success rates of craniofacial osseointegrated implants are not uniform throughout the craniofacial area. A better understanding of their clinical behaviour is needed. This article investigates current perspectives on the application of endosseous implants in the restoration of craniofacial defects. An online search was completed for the time period from 1966 to 2007, along with a manual search, to locate relevant peer-reviewed articles and textbooks published in English. A review of published reports of craniofacial application of endosseous implants in irradiated and nonirradiated tissue sites showed a strong correlation between anatomic sites and clinical success. Maxillofacial prosthetic considerations are also reviewed.     

Revisional Surgery or Pharmacotherapy for Insufficient Weight Loss and Weight Regain After Primary Bariatric Procedure: a Descriptive Study

Obesity Surgery - Bariatric surgery is the most effective and durable treatment option for clinically severe obesity. Unfortunately, some degree of weight regain (WR) is common after nadir weight...     

Tumor-induced mechanical hyperalgesia involves CGRP receptors and altered innervation and vascularization of DsRed2 fluorescent hindpaw tumors

Functional and anatomical relationships among primary afferent fibers, blood vessels, and cancers are poorly understood. However, recent evidence suggests that physical and biochemical interactions between these peripheral components are important to both tumor biology and cancer-associated pain. To determine the role of these peripheral components in a mouse model of cancer pain, we quantified the change in nerve and blood vessel density within a fibrosarcoma tumor mass using stereological analysis of serial confocal optical sections of immunostained hind paw. To this end we introduced the Discoma coral-derived red fluorescent protein (DsRed2) into the NCTC 2472 fibrosarcoma line using the Sleeping Beauty transposon methodology, thus providing a unique opportunity to visualize tumor-nerve-vessel associations in context with behavioral assessment of tumor-associated hyperalgesia. Tumors from hyperalgesic mice are more densely innervated with calcitonin gene related peptide (CGRP)-immunoreactive nerve fibers and less densely vascularized than tumors from non-hyperalgesic mice. As hyperalgesia increased from Day 5 to 12 post-implantation, the density of protein gene product 9.5 (PGP9.5)-immunoreactive nerves and CD31-immunoreactive blood vessels in tumors decreased, whereas CGRP-immunoreactive nerve density remained unchanged. Importantly, intra-tumor injection of a CGRP1 receptor antagonist (CGRP 8-37) partially blocked the tumor-associated mechanical hyperalgesia, indicating that local production of CGRP may contribute to tumor-induced nociception through a receptor-mediated process. The results describe for the first time the interaction among sensory nerves, blood vessels and tumor cells in otherwise healthy tissue, and our assessment supports the hypothesis that direct tumor cell-axon communication may underlie, at least in part, the occurrence of cancer pain.     

Robotic Partial Nephrectomy with Superselective Versus Main Artery Clamping: A Retrospective Comparison

Background

Concerns have been raised regarding partial nephrectomy (PN) techniques that do not occlude the main renal artery.

Objective

Compare the perioperative outcomes of superselective versus main renal artery control during robotic PN.

Design, setting, and participants

A retrospective analysis of 121 consecutive patients undergoing robotic PN using superselective control (group 1, n = 58) or main artery clamping (group 2, n = 63).

Intervention

Group 1 underwent tumor-specific devascularization, maintaining ongoing arterial perfusion to the renal remnant at all times. Group 2 underwent main renal artery clamping, creating global renal ischemia.

Outcome measurements and statistical analysis

Perioperative and functional data were evaluated. The Pearson chi-square or Fisher exact and Wilcoxon rank sum tests were used.

Results and limitations

All robotic procedures were successful, all surgical margins were negative, and no kidneys were lost. Compared with group 2 tumors, group 1 tumors were larger (3.4 vs 2.6 cm, p = 0.004), more commonly hilar (24% vs 6%, p = 0.009), and more complex (PADUA 10 vs 8, p = 0.009). Group 1 patients had longer median operative time (p < 0.001) and transfusion rates (24% vs 6%, p < 0.01) but similar estimated blood loss (200 vs 150 ml), perioperative complications (15% vs 13%), and hospital stay. Group 1 patients had less decrease in estimated glomerular filtration rate at discharge (0% vs 11%, p = 0.01) and at last follow-up (11% vs 17%, p = 0.03). On computed tomography volumetrics, group 1 patients trended toward greater parenchymal preservation (95% vs 90%, p = 0.07) despite larger tumor size and volume (19 vs 8 ml, p = 0.002). Main limitations are the retrospective study design, small cohort, and short follow-up.

Conclusions

Robotic PN with superselective vascular control enables tumor excision without any global renal ischemia. Blood loss, complications, and positive margin rates were low and similar to main artery clamping. In this initial developmental phase, limitations included more perioperative transfusions and longer operative time. The advantage of superselective clamping for better renal function preservation requires validation by prospective randomized studies.

Patient summary

Preserving global blood flow to the kidney during robotic partial nephrectomy (PN) does not lead to a higher complication rate and may lead to better postoperative renal function compared with clamped PN techniques.