Expansion of CD27high plasmablasts in transverse myelitis patients that utilize VH4 and JH6 genes and undergo extensive somatic hypermutation.

Patients with the autoimmune disease multiple sclerosis (MS) typically present with the clinically isolated syndromes (CIS) transverse myelitis (TM) or optic neuritis (ON). B-cell disturbances have been well documented in patients with MS and CIS patients with ON, but not in CIS patients with TM, despite the fact that these patients have the worst clinical outcome of all CIS types. The goal of this study was to characterize the B-cell populations and immunoglobulin genetics in TM patients. We found a unique expansion of CD27(high) plasmablasts in both the cerebrospinal fluid and periphery of TM patients that is not present in ON patients. Additionally, plasmablasts from TM patients show evidence for positive selection with increased somatic hypermutation accumulation in VH4(+) B cells and receptor editing that is not observed in ON patients. These characteristics unique to TM patients may impact disease severity and progression.

Fluorescence-labeled reporter gene in transgenic mice provides a useful tool for investigating cutaneous innervation.

B6.Cg-Tg(Thy1-YFP)16Jrs/J transgenic mice were created to express the yellow fluorescent protein gene driven by a mouse Thy1 promoter that labeled motor and sensory neurons such that individual nerves could be followed. These mice were used to identify nerves in the skin that innervate the erector pili and panniculus carnosus muscle. Whole mounts demonstrated yellow fluorescent protein expression in nerves of the skin, which was confirmed by labeling the neuromuscular junction with fluorescinated α-bungarotoxin. Frozen and paraffin-embedded skin sections revealed innervation of the panniculus carnosus muscle. Paraffin sections labeled with an anti-green fluorescent protein antibody revealed innervation of the panniculus carnosus as well as the erector pili muscle and around the hair follicle bulge.

Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy.

OBJECTIVE: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy. METHODS: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored. RESULTS: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed. CONCLUSION: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.

Esophageal aspiration of air through the drain tube of the ProSeal laryngeal mask.

IMPLICATIONS: Two patients experienced partial upper airway obstruction while breathing spontaneously with the ProSeal laryngeal mask airway. This resulted in esophageal aspiration of air through the drain tube.

Mesenteric and skeletal muscle microvascular responsiveness in subacute sepsis.

This study was performed to assess the effects of subacute sepsis in rats on the in vitro reactivity of arterioles (internal diameter, 100-150 microm) to alpha1- and alpha2-adrenergic stimulation and to angiotensin II. Male Sprague-Dawley rats were rendered septic by intraperitoneal implantation of a gelatin capsule containing sterile rat feces and 1 x 10(6) viable colony forming units of Escherichia coli. Control rats underwent sham laparotomy and implantation of a gelatin capsule containing only sterile feces. In vitro reactivity of arterioles from mesentery and skeletal muscle were studied 48 h later in a pressurized (50 mmHg) no flow state using videomicroscopy. Subacute sepsis decreased the contractile response of nonprecontracted microvessels from both anatomical sites to phenylephrine (both p < .01 versus control) and blunted the relaxation response to staurosporine (both p < .01), an inhibitor of protein kinase C. The small contraction to angiotensin II of mesenteric vessels was inhibited by sepsis (p < .05) but was unaltered in the skeletal muscle microcirculation. In the precontracted mesenteric microvessels from septic rats, endothelium-dependent relaxation to clonidine and to adenosine 5'-diphosphate were decreased (both p < .01 versus control), whereas in skeletal muscle microvessels, clonidine and adenosine 5'-diphosphate elicited constriction (both p < .01). Relaxation to the endothelium independent vasodilators sodium nitroprusside and pinacidil was preserved across all vessels. In conclusion, mesenteric and skeletal muscle microvascular responses to angiotensin II and alpha1- and alpha2-adrenergic stimulation are altered in subacute sepsis. This may in part lead to systemic hypotension and altered organ perfusion during states of chronic sepsis.

Chronic septicemia alters alpha-adrenergic mechanisms in the coronary circulation.

The purpose of the present study was to determine the effect of chronic sepsis on alpha-adrenergic responsiveness in the coronary microcirculation. Male Sprague-Dawley rats (n = 6) were made septic by intraperitoneal implantation of a gelatin capsule containing 35 mg sterile rat feces and 1 x 10(8) viable colony-forming units of Escherichia coli (strain Sm 018). Control rats (n = 6) were implanted with capsules containing only sterile feces. Forty-eight hours after surgery, subepicardial coronary arterioles (80-170 mm) were isolated. In vitro arteriolar responses were studied in a pressurized, no-flow state with video-microscopy. Chronic sepsis decreased the contractile responses to the alpha 1-adrenoceptor agonist phenylephrine and the protein kinase C (PKC) activator 12-deoxyphorbol 13-isobutyrate 20-acetate. Relaxation responses to the alpha 2-adrenoceptor agonist clonidine, the endothelium-dependent vasodilator adenosine 5'-diphosphate, and the PKC inhibitor staurosporine were reduced, but the relaxation to the endothelium-independent cyclic GMP-mediated vasodilator sodium nitroprusside was preserved. Relaxation to clonidine was inhibited by endothelial denudation or after blockade of nitric oxide synthase. Chronic sepsis may reduce alpha 2-adrenoceptor-mediated relaxation of coronary microvessels by causing endothelial dysfunction. The alpha 1-adrenergic mechanism is downregulated, possibly due to alterations in the receptor and/or downstream signal transduction via PKC.

Dantrolene, an inhibitor of intracellular calcium release, fails to increase survival in a rat model of intra-abdominal sepsis.

OBJECTIVE: Increased release of intracellular calcium has been implicated in cell death and organ failure in endotoxemia and sepsis. We sought to test this hypothesis in a rat model of antibiotic-treated intraperitoneal sepsis with the use of dantrolene sodium, a specific inhibitor of intracellular calcium release. DESIGN: A prospective, randomized controlled trial. SETTING: An experimental animal laboratory in a university hospital. SUBJECTS: Two hundred fourteen male Sprague-Dawley rats. INTERVENTIONS: Rats were rendered septic by intraperitoneal implantation of sterile feces mixed with live Escherichia coli and allocated to control, vehicle, or dantrolene treatment. A separate group of rats had arterial catheters implanted to allow blood sampling for determination of circulating tumor necrosis factor (TNF)-alpha and lactate concentrations. Additional rats were randomized to receive vehicle or dantrolene after intravenous injection of endotoxin. MEASUREMENTS AND MAIN RESULTS: Over the 7-day study period, survival was significantly worse among rats that received dantrolene at a dose of 10 mg/kg, irrespective of whether treatment was started before or after induction of peritonitis. Mean whole blood lactate for each group peaked at 6 hrs after induction of infection. There were no significant differences in lactate concentration among the groups at any of the time points examined. Similarly, there were no differences among any of the groups for circulating concentrations of TNF-alpha. In rats challenged with endotoxin, dantrolene affected neither survival nor circulating concentrations of TNF-alpha. CONCLUSIONS: We conclude that dantrolene decreases survival in bacterial sepsis and has no effect on survival in endotoxemia in rats. The importance of excessive intracellular calcium release in sepsis remains to be elucidated.

Dynamics of skin blood flow in human sepsis.

OBJECTIVE: The study was undertaken to determine if sepsis alters the pattern of vasomotion and reactive hyperaemia in the skin. DESIGN: This was a prospective, observational study. SETTING: The study was performed in the medical and surgical intensive care units of a tertiary referral hospital. PATIENTS AND PARTICIPANTS: 11 patients with sepsis (using Bone's criteria [1]), were compared with 19 patients recovering from coronary artery bypass grafting who were used as non-septic controls. Nineteen normal volunteers were also studied. MEASUREMENTS AND RESULTS: Skin blood flow was measured on the forearm using laser Doppler flowmetry at rest and after 2 min arterial occlusion with a tourniquet. The resting blood signal was analyzed by calculating the mean skin blood flow, the power of the skin blood flow signal (variance) and the power spectrum. The rate of recovery after arterial occlusion was determined by calculating the peak increase in skin blood flow and the time constant of the decay of skin hyperaemia back to baseline flow. Patients with sepsis had a mean skin blood flow of 6.24 (3.48) ml min-1 per 100 g tissue compared with 4.35 (1.41) ml min-1 per 100 g tissue for the patients after coronary artery bypass grafting (p < 0.05). The septic patients also showed a marked increase in the fraction of total power in the 0.1-0.15 Hz frequency band (0.19 (0.17) versus 0.068 (0.033), p < 0.05), a decreased peak hyperaemic response (40 (23)% increase in flow above baseline after cuff release versus 147 (19)%) and a prolonged time constant for recovery from hyperaemia (22.8 (12.7) versus 11.7 (8.5) seconds, p < 0.05). These results imply an increased local rather than central control of skin blood flow. CONCLUSION: The laser Doppler flowmeter allows local rather than global haemodynamics to be studied. Abnormalities of skin blood flow control are found in sepsis, and this technique may prove useful to monitor the effects of treatment, especially if the use of laser Doppler flowmetry can be extended to other organs at risk of damage during sepsis such as gastro-intestinal mucosa.

Nurse-physician collaboration and decision outcomes in transplant ambulatory care settings.

OBJECTIVE: This study examined the nature of nurse-physician collaborative practice as reflected in problems presented by transplant patients in telephone contacts with clinical nurse specialists (CNSs). DESIGN: Exploratory descriptive study. SAMPLE/SETTING: The sample consisted of 202 renal and renal-pancreas transplant recipients who telephoned nurses at the outpatient clinic of a tertiary care medical center. METHODS: Over a period of 6 weeks, using a data collection form, nurse specialists recorded the types and frequencies of problems described by transplant patients via telephone interaction and categorized the outcomes of decisions. RESULTS: Of the 437 calls, averaging 2.16 calls per patient, problems were classified as general questions (46%), medication related (32%), and clinical signs and symptoms (22%) such as fever, rejection, colds, and urinary tract infections. Decision outcomes (n = 354) categorized as independent or collaborative for problem resolution were: CNS only (80%), MD only (11%), and collaborative (9%). CONCLUSIONS: Resolution of 80% of patients' problems presented in telephone interactions shows that advanced practice nurses play a pivotal role in the delivery of care to outpatient transplant recipients. Independent decision making on the part of the nurse occurs within the context of ongoing collaboration and communication with physician colleagues.

Clinical nurse specialist: a facilitator for clinical research.

The role of the clinical nurse specialist is continuing to expand to include participation in clinical research. There is, however, a lack of clinical researchers available to conduct nursing research. A clinical nurse specialist with a joint appointment between a clinical and an academic setting can facilitate clinical research through collaboration. Such collaborative efforts can result in improved patient care and nursing practice. This article describes several major collaborative models used to join the academic and practice settings and discusses their strengths and weaknesses. It also describes in detail a collaborative approach in which the clinical nurse specialist play a more pivotal role by acting as a facilitator for the collaboration. We discuss the formation of the collaborative team, the roles of the participants, and the research plan of the team. Suggestions for implementing this model in other settings are offered.