Intracranial effects of endotracheal suctioning in the acute phase of head injury.

In patients with head injury, endotracheal suctioning (ETS) is a potentially dangerous procedure, because it can increase intracranial pressure (ICP). The purpose of this prospective nonrandomized study was to evaluate the impact of ETS on intracranial dynamics in the acute phase of head injury. Seventeen patients with severe head injury (Glasgow Coma Score < or = 8, range 4-8), sedated and mechanically ventilated, were studied during the first week after trauma. Single-pass ETS maneuver (with a 16-French catheter, negative pressure of 100 mm Hg, and duration of less than 30 seconds) was performed 60 seconds after the FiO2 was increased to 100%. After ETS, FiO2 was maintained at 100% for another 30 seconds. Before and after ETS, arterial blood gases and jugular oxygen saturation (S(j)O2), ICP, and mean arterial pressure (MAP) were measured and cerebral perfusion pressure (CPP) was calculated. A total of 131 ETS episodes, which consisted of repeated assessment of each patient, were analyzed. Six patients in 20 cases coughed and/or moved during ETS because of inadequate sedation. After ETS, ICP increased from 20 +/- 12 to 22 +/- 13 mm Hg in well-sedated patients and from 15 +/- 9 to 28 +/- 9 mm Hg in patients who coughed and/or moved (mean change, 2 +/- 6 versus 13 +/- 6 mm Hg, P <.0001). CPP and S(j)O2 increased in well-sedated patients (from 78 +/- 16 to 83 +/- 19 mm Hg, and from 71 +/- 10 to 73 +/- 13%, respectively) and decreased in patients who reacted to ETS (from 79 +/- 14 to 72 +/- 14 mm Hg and from 69 +/- 7 to 66 +/- 9%, respectively), and the differences were significant (mean change, CPP: 5 +/- 14 versus -7 +/- 15 mm Hg, P =.003; (S(j)O2) 2 +/- 5 vs. -3 +/- 5%, P <.0001). In well-sedated patients, endotracheal suctioning caused an increase in ICP, CPP, and S j O 2 without evidence of ischemia. In contrast, in patients who coughed or moved in response to suctioning, there was a slight and significant decrease in CPP and S(j)O2. In the case of patients with head injuries who coughed or moved during endotracheal suctioning, we strongly suggest deepening the level of sedation before completing the procedure to reduce the risk of adverse effects.     

Ventromedial Hypothalamic Nitric Oxide Production Is Necessary for Hypoglycemia Detection and Counterregulation

OBJECTIVE

The response of ventromedial hypothalamic (VMH) glucose-inhibited neurons to decreased glucose is impaired under conditions where the counterregulatory response (CRR) to hypoglycemia is impaired (e.g., recurrent hypoglycemia). This suggests a role for glucose-inhibited neurons in the CRR. We recently showed that decreased glucose increases nitric oxide (NO) production in cultured VMH glucose-inhibited neurons. These in vitro data led us to hypothesize that NO release from VMH glucose-inhibited neurons is critical for the CRR.

RESEARCH DESIGN AND METHODS

The CRR was evaluated in rats and mice in response to acute insulin-induced hypoglycemia and hypoglycemic clamps after modulation of brain NO signaling. The glucose sensitivity of ventromedial nucleus glucose-inhibited neurons was also assessed.

RESULTS

Hypoglycemia increased hypothalamic constitutive NO synthase (NOS) activity and neuronal NOS (nNOS) but not endothelial NOS (eNOS) phosphorylation in rats. Intracerebroventricular and VMH injection of the nonselective NOS inhibitor N^G-monomethyl-l-arginine (l-NMMA) slowed the recovery to euglycemia after hypoglycemia. VMH l-NMMA injection also increased the glucose infusion rate (GIR) and decreased epinephrine secretion during hyperinsulinemic/hypoglycemic clamp in rats. The GIR required to maintain the hypoglycemic plateau was higher in nNOS knockout than wild-type or eNOS knockout mice. Finally, VMH glucose-inhibited neurons were virtually absent in nNOS knockout mice.

CONCLUSIONS

We conclude that VMH NO production is necessary for glucose sensing in glucose-inhibited neurons and full generation of the CRR to hypoglycemia. These data suggest that potentiating NO signaling may improve the defective CRR resulting from recurrent hypoglycemia in patients using intensive insulin therapy.Intensive insulin therapy significantly reduces the onset and progression of hyperglycemia-related complications in patients with type 1 and advanced type 2 diabetes. However, intensive insulin therapy also causes a clinically adverse effect: hypoglycemia (1). Powerful neuroendocrine and autonomic counterregulatory mechanisms protect the brain from hypoglycemia (2,3). These protective mechanisms, known as the counterregulatory response (CRR) to hypoglycemia, involve the release of hormones (e.g., glucagon, epinephrine) that restore euglycemia by stimulating hepatic glucose production and inhibiting peripheral glucose uptake (3). Although the physiology of the CRR is well understood, the underlying cellular mechanisms by which the brain senses hypoglycemia and initiates the CRR remain elusive.During hypoglycemia, central and peripheral glucose sensors detect declining glucose levels (4). In the brain, the ventromedial hypothalamus, which includes the arcuate nucleus and the ventromedial nucleus (VMN), is important in the initiation of the CRR (5–7). This region contains specialized glucose-sensing neurons (GSNs). Ventromedial hypothalamic (VMH) GSN electrical activity is regulated by physiologically relevant changes in extracellular glucose levels (8–11). Glucose-excited neurons decrease, whereas glucose-inhibited neurons increase, their input resistance, membrane potential, and action potential frequency when extracellular glucose is reduced (10). Many studies suggest that VMH glucose-inhibited neurons play a critical role in the control of the CRR (4). For example, the response of VMH glucose-inhibited neurons to decreased glucose is impaired under conditions where the CRR is impaired (e.g., recurrent hypoglycemia) (12,13).Nitric oxide (NO) is a gaseous messenger produced by NO synthase (NOS). Two classes of NOS have been identified in the brain: the inducible NOS (iNOS) and the constitutive NOS, which includes the neuronal NOS (nNOS) and endothelial NOS (eNOS) isoforms (14). Hypothalamic NO is involved in the regulation of food intake and glucose homeostasis (15–18). In support of this, we have recently shown that VMH glucose-inhibited neurons produce NO via nNOS in response to decreased extracellular glucose levels (19,20). Therefore, in this study, we test the hypothesis that NO production by VMH glucose-inhibited neurons is necessary for the CRR to hypoglycemia. We tested this hypothesis using a combination of in vivo and in vitro techniques in wild-type rats and mice as well as in transgenic nNOS and eNOS knockout mice.     

Genetic aberrations of NAT2 and chromosome 8: their association with progression in transitional cell carcinoma of the urinary bladder

INTRODUCTION/OBJECTIVE: N-acetyltransferase 2 (NAT2), mapped to 8p22, is a polymorphic enzyme which metabolizes aromatic amines. Loss of heterozygosity of 8p22 is associated with an increased risk of bladder cancer. This study evaluated NAT2 and chromosome 8 in sequential tumours from bladder cancer patients to determine if NAT2 alterations increase the risk of progression. MATERIALS AND METHODS: Thirty-seven sequential carcinomas from 19 patients were assessed using fluorescence in situ hybridization. RESULTS: Five carcinomas showed loss of NAT2; 4 of these were from pTa/pT1 tumours. Polysomy 8 was observed in 4 of 14 (29%) primary carcinomas (pTa/pT1), in 4 of 12 (33%) pTa/pT1 recurrences, and in 90% (9/10) of the detrusor muscle invasive tumours (pT2+). 6 of 8 (75%) locally invasive tumours with polysomy 8 were from patients who subsequently developed disease progression (pT2+). In total, 13.5% (5/37) of the carcinomas were abnormal for NAT2, and 46% (17/37) were abnormal for chromosome 8 copy number. Polysomy 8 was associated with high grade (p = 0.01) and stage (p = 0.03) and disease progression (p = 0.03). CONCLUSION: Whilst there does not appear to be an association between loss of NAT2 and risk of progression in transitional cell carcinoma, the high rate of polysomy of chromosome 8 implies that other genes on this chromosome significantly influence disease progression.     

Delayed Complications after Anterior Craniofacial Resection of Malignant Skull Base Tumors

Objective To report complications occurring at least 6 months after completion of treatment for patients with anterior skull base malignancy undergoing anterior craniofacial resection (CFR). Design Retrospective review of medical records of all patients undergoing traditional CFR for treatment of anterior skull base malignancy from 2002 through 2011. Setting Massachusetts General Hospital/Massachusetts Eye and Ear Infirmary Cranial Base Center. Participants Thirty-one consecutive patients who had at least 18 months of follow-up for analysis were reviewed. All patients underwent traditional CFR. A total of 28 patients received postoperative proton beam radiation therapy. Eleven patients received adjuvant chemotherapy. Main Outcome Measures A delayed complication was any complication occurring at least 6 months after the completion of treatment. Results Seventeen patients had delayed complications. Orbital complications were the most common type (13 patients) followed by issues with wound healing (6 patients). The most common orbital complication was epiphora (7 patients). The most common wound complication was a nasocutaneous fistula (5 patients). Conclusions Patients with anterior skull malignancy can develop complications months to years after the completion of treatment. Therefore, it is important to continue to follow and report complications for several years when deciding on the optimal approach for treatment of these patients.     

Postimplant Behavior of Lightweight Polypropylene Meshes in an Experimental Model of Abdominal Hernia

Background. Over the years, reticular prostheses have undergone changes in their structure and composition to give rise to today's partially absorbable lightweight meshes. This study was designed to assess the biological and biomechanical behavior of these prostheses to establish whether they offer any advantages over nonabsorbable lightweight polypropylene prostheses. Materials and Methods. 7 × 5 cm defects were created in the anterior abdominal wall of New Zealand White rabbits and repaired by securing different prostheses to the edges of the defect with a running 4/0 polypropylene suture. The lightweight biomaterials compared were two nonabsorbable meshes: Parietene® and Optilene elastic®, and two partially absorbable prostheses: Vypro II® and Ultrapro®. At 14 and 90 days postimplant, tissue/prosthesis specimens were subjected to histological, immunohistochemical, shrinkage, and biomechanical analyses. Results. Adhesion formation on the peritoneum-facing surface of the meshes was significantly less extensive in the meshes with absorbable components at 90 days postimplant. The newly formed tissue around the prosthetic filaments was comprised of collagen fibers, fibroblasts, blood vessels, and macrophages. The partially absorbable meshes showed higher macrophage proportions (due to remnants of absorbable material and their structure) than the nonabsorbable meshes at 90 days, although differences were not significant. At 90 days postimplant, similar tensile strengths were recorded for all the implants. Conclusions. All the prosthetic materials induced good host tissue ingrowth, with no significant differences in tensile strength observed. Our findings suggest that partially absorbable lightweight prostheses could offer advantages over nonabsorbable lightweight meshes since less foreign material persists in the recipient, improving abdominal wall compliance.     

Serum micronutrients and prealbumin during development and recovery of chemotherapy‐induced peripheral neuropathy

Chemotherapy‐induced peripheral neuropathy (CIPN) is a frequent adverse event. Nutritional status can become impaired in cancer patients, potentially contributing to neuropathy's evolution. Our aim was to evaluate serum micronutrients and prealbumin in a cohort of 113 solid‐cancer patients receiving platinum and taxane compounds during the development and recovery of neuropathy, up to 1 year after finishing treatment. CIPN was graded according to Total Neuropathy Score^© and NCI.CTCv3 at T0 (baseline), T1 (1–3 months), and T12 (12 months) after chemotherapy. CIPN was classified as asymptomatic (< grade 2) or symptomatic (≥2). CIPN recovery was defined as ≥1 grade improvement at T12. Symptomatic CIPN developed in 52% of patients. Symptomatic patients presented a higher increase in TNSc (p < 0.001), in TNSr^© (p < 0.001), and decrease in sural (p < 0.001) and radial nerve conduction (p < 0.001). No significant differences with any of the micronutrients were observed along T0‐T1 period between severity or chemotherapy groups. By T12, symptomatic patients without recovery had a decrease in vitamin E levels (p = 0.019) and prealbumin (p = 0.062) compared with those symptomatic that improved. A correlation between the variation of vitamin E and prealbumin at T0‐T1 (r = 0.626, p = 0.001) and T1‐T12 (r = 0.411, p = 0.06) was observed. After chemotherapy treatment, the improvement of patients displaying symptomatic neuropathy is related to vitamin E and prealbumin serum levels. Our results suggest that nutritional status can play a role in CIPN recovery.     

Evidence That Hyperglycemia After Recovery From Hypoglycemia Worsens Endothelial Function and Increases Oxidative Stress and Inflammation in Healthy Control Subjects and Subjects With Type 1 Diabetes

Currently there is debate on whether hypoglycemia is an independent risk factor for atherosclerosis, but little attention has been paid to the effects of recovery from hypoglycemia. In normal control individuals and in people with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normoglycemia or hyperglycemia for another 2 h and then maintaining normal glycemia for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. Recovery with normoglycemia is accompanied by a significant improvement in endothelial dysfunction, oxidative stress, and inflammation, which are affected by hypoglycemia; however, a period of hyperglycemia after hypoglycemia worsens all of these parameters, an effect that persists even after the additional 6 h of normoglycemia. This effect is partially counterbalanced when hyperglycemia after hypoglycemia is accompanied by the simultaneous infusion of vitamin C, suggesting that when hyperglycemia follows hypoglycemia, an ischemia–reperfusion-like effect is produced. This study shows that the way in which recovery from hypoglycemia takes place in people with type 1 diabetes could play an important role in favoring the appearance of endothelial dysfunction, oxidative stress, and inflammation, widely recognized cardiovascular risk factors.Recent evidence suggests that hypoglycemia may play an important role in the vascular complications of diabetes (1). Hypoglycemia causes oxidative stress (2), inflammation (3), and endothelial dysfunction (4). Oxidative stress is considered the key player in the pathogenesis of diabetes complications (5). During hyperglycemia, oxidative stress is produced at the mitochondrial level (5), similarly as in hypoglycemia (2). Therefore, oxidative stress might be considered the common factor linking hyperglycemia, hypoglycemia, and the vascular complications of diabetes. Consistent with this hypothesis is the evidence that hyperglycemia (6) and hypoglycemia both produce endothelial dysfunction and inflammation through the generation of oxidative stress (4,7). Endothelial dysfunction and inflammation are well-recognized pathogenic factors for vascular disease, particularly in diabetes (8).There is, however, evidence that free radical production rises, not only during hypoglycemia but particularly during glucose reperfusion after hypoglycemia (9). In both mice and cultured neurons, hypoglycemia, followed by different concentrations of glucose reperfusion, has been linked to a degree of superoxide production and neuronal death that increased proportionally with glucose concentrations during the reperfusion period (9).Until now, little attention has been given to studying the effects of recovery from hypoglycemia. The aim of this study was to evaluate these effects and, in particular, to determine if the level of glycemia reached during recovery could have a different impact, in vivo, on oxidative stress generation, inflammation, and endothelial function.     

Reverse elephant trunk technique: a novel approach to pseudoaneurysm repair

Traditional surgical access to the upper descending aorta is via a left thoracotomy. For postcoarctation pseudoaneurysm repair, this approach is difficult because of the risk of rupture while dissecting the aorta for proximal and distal control. Access from a median sternotomy may be safer, but is difficult because of the depth of the wound and because of the angle of approach to the distal aspect of the repair site. We describe a novel approach via a median sternotomy incision, using circulatory arrest and "elephant trunk" principles to achieve tube graft replacement of the aneurysmal section of aorta.     

Cytokines and growth factors in keratinocytes and sweat glands in chronic venous leg ulcers. An immunohistochemical study

The role of growth factors and cytokines in the impaired healing of chronic leg ulcers remains uncertain. The aim of this study was to determine whether changes in the amount and location of cytokines and growth factors may be associated with impaired healing in chronic leg ulcers. Biopsies from leg ulcers of 21 patients and from normal skin of nine healthy volunteers were examined immunohistochemically for selected growth factors and cytokines. Greater staining intensity was found in keratinocytes at the edges of ulcers compared to normal skin, or skin adjacent to the ulcers. Staining at the ulcer edge was more intense in nonhealing ulcers for only vascular endothelial growth factor and platelet-derived growth factor, whereas staining in the adjacent skin was more intense for all factors in the nonhealing phase. For all factors staining was cytoplasmic, suggesting production in these areas. This study shows up-regulation of the production of cytokines and growth factors in keratinocytes of chronic leg ulcers that is greater when the ulcers are nonhealing.