Systematic review: Early versus late dangling after free flap reconstruction of the lower limb.

INTRODUCTION AND AIMS: Dangling regimes after free flap surgery to the lower limb vary between centres and clinicians. There is currently no accepted gold standard. This review examines the evidence for early versus late post-operative dangling after free flap reconstruction of the lower limb. The secondary aim is to evaluate the regimes used. MATERIAL AND METHODS: Medline, Embase and the Cochrane library were searched for all studies on dangling or rehabilitation after free flap reconstruction in the lower limb (December 2015). All studies outlining a clear dangling regime were included. Data were extracted by two authors independently and analysed using the software package Review Manager (RevMan 5). All authors were contacted for further information. RESULTS: 197 patients were included from 8 studies: 1 randomized, 6 cohort and 1 case-series. Although some studies did not state the aetiology, of those that did; 42% were trauma, 31% oncology, 20% complex wounds and 7% infection. The majority of flaps were latissimus dorsi, 18% parascapular, 15% anterolateral thigh and the remainder was mixed. Forty-eight percent of patients dangled on post-operative day (POD) 7, 29% on day 6, 4% on day 5 and 18% on day 3, with varying regimes. A meta-analysis of comparable studies showed circulatory benefit after 4 days of dangling using tissue oxygen saturation as a measure. Four flap failures (2.0%) were reported. CONCLUSIONS: There is physiological benefit in post-operative dangling. A 3-day flap training regime is sufficient for physiological training. However, the optimal flap training regime remains unclear. It may be appropriate to start dangling as early as POD 3. More research is needed to determine the optimal time to start dangling and the regime.

Current status and future prospects for cultured limbal tissue transplants in Australia and New Zealand.

Cultured limbal tissue transplants have become widely used over the last decade as a treatment for limbal stem cell deficiency (LSCD). While the number of patients afflicted with LSCD in Australia and New Zealand is considered to be relatively low, the impact of this disease on quality of life is so severe that the potential efficacy of cultured transplants has necessitated investigation. We presently review the basic biology and experimental strategies associated with the use of cultured limbal tissue transplants in Australia and New Zealand. In doing so, we aim to encourage informed discussion on the issues required to advance the use of cultured limbal transplants in Australia and New Zealand. Moreover, we propose that a collaborative network could be established to maintain access to the technology in conjunction with a number of other existing and emerging treatments for eye diseases.

Clinical study on cholesterol-lowering effect of RYR Cholestin among Americans with moderate hy-percholesterolemia / 上海预防医学

[Objective] To evaluate lipid -lowering efficacy and safety of RYR Cholestin , or Monascus purpureus (Red Yeast) Rice, in Americans with moderate hypercholesterolemia. [Methods] This study was an open-label, self-control, and multi-center clinical trial.A total of 187 subjects were entered into this trial (serum LDL-Cholesterol 3.50~4.92 mmol/L,total cholesterol 5.18~7.25 mmol/L, male:female=116∶71) , of whom 162 completed the study .Subjects were placed on the NCEP Step I Diet throughout the study and RYR Cholestin (2.4 g/day) was administered for 8 weeks following initial 4-week diet control . [ Results] Being on the diet alone for 4 weeks resulted in no significant changes in serum lipids .RYR Cholestin treatment for 8 weeks reduced serum total cholesterol , LDL-Cholesterol and triglycerides by 16 .6%, 24 .0%, and 25 .2%, respectively , and increased HDL-Cholesterol by 14 .3%( all P<0 .001 ) .There were 97 .5% of patients having ≥10% improvement in at least one of lipid risk factors, and 79.0%having ≥20% improvement.Discontinuation of RYR Cholestin intervention for 14 d led to a return of serum lipids to baseline of pre -study .And 29 possible product -related mild adverse re-actions were reported . [ Conclusion] RYR Cholestin is well tolerated and effective in reducing total and LDL-Cholesterol, and triglycerides, as well as in increasing HDL-Cholesterol in hypercholesterolemic patients, but those indicators return to the beginning baseline when the treatment is discontinued .

Can theory be embedded in visual interventions to promote self-management? A proposed model and worked example.

Nurses are increasingly involved in a range of strategies to encourage patient behaviours that improve self-management. If nurses are to be involved in, or indeed lead, the development of such interventions then processes that enhance the likelihood that they will lead to evidence that is both robust and usable in practice are required. Although behavioural interventions have been predominantly based on written text or the spoken word increasing numbers are now drawing on visual media to communicate their message, despite only a growing evidence base to support it. The use of such media in health interventions is likely to increase due to technological advances enabling easier and cheaper production, and an increasing social preference for visual forms of communication. However, the development of such media is often highly pragmatic and developed intuitively rather than with theory and evidence informing their content and form. Such a process may be at best inefficient and at worst potentially harmful. This paper performs two functions. Firstly, it discusses and argues why visual based interventions may be a powerful media for behaviour change; and secondly, it proposes a model, developed from the MRC Framework for the Development and Evaluation of Complex Interventions, to guide the creation of theory informed visual interventions. It employs a case study of the development of an intervention to motivate involvement in a lifestyle intervention among people with increased cardiovascular risk. In doing this we argue for a step-wise model which includes: (1) the identification of a theoretical basis and associated concepts; (2) the development of visual narrative to establish structure; (3) the visual rendering of narrative and concepts; and (4) the assessment of interpretation and impact among the intended patient group. We go on to discuss the theoretical and methodological limitations of the model.

Multimodal optical molecular image reconstruction with frequency domain measurements.

Multimodality molecular imaging is becoming more and more important to understand both the structural and the functional characteristics of tissue, organs and tumors. So far, invasive nuclear methods utilizing ionizing radiation have been the "gold standard" of molecular imaging. We investigate non-contact, non-invasive, patient-tolerant and inexpensive near infrared (NIR) frequency domain optical tomography (FDOT) as a functional complement to structural X-ray computed tomography (CT) data. We show a novel multifrequency NIR FDOT approach both in transmission and reflectance mode and employ radiative transport equation (RTE) for 3D reconstruction of a target with novel fluorescent gold nanoshell indocyanine green (NS ICG) in an ex vivo nude mouse. The results demonstrate that gold NS ICG with multifrequency NIR FDOT is a promising fluorophore for multimodal optical molecular image reconstruction.

Epithelial defect, diffuse lamellar keratitis, and epithelial ingrowth following post-LASIK epithelial toxicity.

This case reports an association between 2 uncommon flap complications in 1 eye related to epithelial toxicity and subsequent epithelial defect secondary to prolonged intraoperative exposure to topical anesthesia. A patient had hyperopic laser in situ keratomileusis (LASIK) for the correction of +2.75 +1.75 x 70 in the left eye. Because of the patient's anxiety and movement, additional topical local anesthesia was used and the flap remained reflected for 5 minutes. Immediately postsurgery, a toxic appearance was noted in the epithelium of the LASIK flap; 24 hours later, a large central epithelial defect was identified. Three days post- LASIK, the epithelial defect had healed but diffuse lamellar keratitis was noted in the interface, particularly underlying the location of the original epithelial defect. Over 6 weeks, a self-limiting epithelial ingrowth developed in the inferior interface. Fourteen months post-LASIK, the uncorrected visual acuity was 6/9 with a residual refraction of +0.50 +0.50 x 90.

Highly purified mutant E112K of cholera toxin elicits protective lung mucosal immunity to diphtheria toxin.

We demonstrated that the mutant of cholera toxin (mCT) E112K which was LPS-free supported the induction of protective immunity in mucosal (e.g. lung lavage) and systemic (e.g. serum) compartments when given nasally with vaccine-grade diphtheria toxoid (DT) to mice. Significant DT-specific mucosal IgA antibody (Ab) and serum IgG, IgA and IgM Ab responses were induced when LPS-depleted mCT E112K or native CT (nCT) was co-administered nasally with DT. The analysis of DT-specific Ab-forming cell (AFC) responses supported the Ab titers and significant numbers of DT-specific IgA AFC were present in the lungs, nasal passages and submandibular glands. Furthermore, DT-specific IgG AFC in cervical lymph nodes (CLN) and the spleen were induced in mice administered with DT nasally with either mCT or nCT. The analysis of antigen-specific T cell responses revealed that increased DT-specific CD4+ T cell proliferative and Th2-type cytokine responses were induced in mice nasally-immunized with DT and the LPS-free form of mCT. The neutralization of diphtheria toxin by Abs showed that DT-specific IgG Ab responses in serum and lung lavages of mice immunized with DT and mCT were protective. Furthermore, it was shown that an IgA-enriched fraction of lung lavages possessed diphtheria toxin-specific neutralizing activity. These results are the first demonstration that nasally co-administered mCT E112K can induce DT-specific protective Ab responses in mucosal compartments (e.g. lung lavages and the lungs).

Resistance of T-cell receptor delta-chain-deficient mice to experimental Candida albicans vaginitis.

Conditions consistent with tolerance or immunoregulation have been observed in experimental Candida albicans vaginal infections. The present study investigated the role of gamma/delta T cells in experimental vaginal candidiasis. Results showed that T-cell receptor delta-chain-knockout mice had significantly less vaginal fungal burden when compared to wild-type mice, suggesting an immunoregulatory role for gamma/delta T cells in Candida vaginitis.

A revisit of mucosal IgA immunity and oral tolerance.

Induction of mucosal immunity by oral immunization with protein antigen alone is difficult: potent mucosal adjuvants, vectors, or other special delivery systems are required. Cholera toxin (CT) has been shown to be an effective adjuvant for the development of mucosal vaccines and, when given with vaccine, induces both mucosal and systemic immune responses via a Th2 cell-dependent pathway. However, and in addition to potential type-I hypersensitivity, a major concern for use of mucosal adjuvants such as CT is that this molecule is not suitable for use in humans because of its inherent toxicity. When we examined the potential toxicity of CT for the central nervous system, both CT and CT-B accumulated in the olfactory nerves/epithelium and olfactory bulbs of mice when given by the nasal route. The development of effective mucosal vaccines for the elderly is also an important issue; however, only limited information is available. When mucosal adjuvanticity of CT was evaluated in aged mice, an early immune dysregulation was evident in the mucosal immune system. The present review discusses these potential problems for effective mucosal vaccine development. Tolerance represents the most common and important response of the host to environmental antigens, including food and commensal bacterial components, for the maintenance of an appropriate immunological homeostasis. We have examined whether Peyer patches could play a more important role for the maintenance of oral tolerance. Using Peyer patch-null mice, we found that mice lacking this gut-associated lymphoid tissue retained their capability to produce secretory IgA antibodies but did not develop normal oral tolerance to protein antigens.

The pulmonary environment promotes Th2 cell responses after nasal-pulmonary immunization with antigen alone, but Th1 responses are induced during instances of intense immune stimulation.

The purpose of this study was to determine the nature of the CD4(+) Th cell responses induced after nasal-pulmonary immunization, especially those coinciding with previously described pulmonary inflammation associated with the use of the mucosal adjuvant, cholera toxin (CT). The major T cell population in the lungs of naive mice was CD4(+), and these cells were shown to be predominantly of Th2 type as in vitro polyclonal stimulation resulted in IL-4, but not IFN-gamma, production. After nasal immunization with influenza Ag alone, Th2 cytokine mRNA (IL-4 and IL-5) levels were increased, whereas there was no change in Th1 cytokine (IL-2 and IFN-gamma) mRNA expression. The use of the mucosal adjuvant, CT, markedly enhanced pulmonary Th2-type responses; however, there was also a Th1 component to the T cell response. Using in vitro Ag stimulation of pulmonary lymphocytes, influenza virus-specific cytokine production correlated with the mRNA cytokine results. Furthermore, there was a large increase in CD4(+) Th cell numbers in lungs after nasal immunization using CT, correlating with the pulmonary inflammatory infiltrate previously described. Coincidentally, both macrophage-inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta mRNA expression increased in the lungs after immunization with Ag plus CT, while only MIP-1beta expression increased when mice were given influenza Ag alone. Our study suggests a mechanism to foster Th1 cell recruitment into the lung, which may impact on pulmonary immune responses. Thus, while Th2 cell responses may be prevalent in modulating mucosal immunity in the lungs, Th1 cell responses contribute to pulmonary defenses during instances of intense immune stimulation.

Cytokines as adjuvants for the induction of mucosal immunity.

Safe nasal vaccines capable of promoting both mucosal and systemic immunity are needed for effective protection against bacterial and viral pathogens. While parenteral cytokine treatment could lead to unwanted toxicity, the nasal delivery route results in low but biologically active serum cytokine levels. Interleukin (IL)-6, IL-1 and IL-12, which promote either Th2- or Th1-type responses, respectively, also enhance systemic immunity to co-administered antigens. The chemoattractants lymphotactin (Lptn), RANTES and defensins also exerted adjuvant activity for systemic immunity when nasally administered with antigens. However, each cytokine or innate factor promoted a distinct pattern of T helper cell responses and corresponding IgG subclass response. Interleukin-12, IL-1, and the chemokines Lptn and RANTES promote mucosal immunity. In contrast, nasal IL-6 and defensins failed to induce mucosal S-IgA Ab responses, suggesting that mechanisms more complex than T cell activation and chemotaxis are required for the development of mucosal immunity after nasal delivery of cytokines.

Elimination of colonic patches with lymphotoxin beta receptor-Ig prevents Th2 cell-type colitis.

Past studies have shown that colonic patches, which are the gut-associated lymphoreticular tissues (GALT) in the colon, become much more pronounced in hapten-induced murine colitis, and this was associated with Th2-type T cell responses. To address the role of GALT in colonic inflammation, experimental colitis was induced in mice either lacking organized GALT or with altered GALT structures. Trinitrobenzene sulfonic acid was used to induce colitis in mice given lymphotoxin-beta receptor-Ig fusion protein (LTbetaR-Ig) in utero, a treatment that blocked the formation of both Peyer's and colonic patches. Mice deficient in colonic patches developed focal acute ulcers with Th1-type responses, whereas lesions in normal mice were of a diffuse mucosal type with both Th1- and Th2-type cytokine production. We next determined whether LTbetaR-Ig could be used to treat colitis in normal or Th2-dominant, IFN-gamma gene knockout (IFN-gamma(-/-)) mice. Four weekly treatments with LTbetaR-Ig resulted in deletion of Peyer's and colonic patches with significant decreases in numbers of dendritic cells. This pretreatment protected IFN-gamma(-/-) mice from trinitrobenzene sulfonic acid-induced colitis; however, in normal mice this weekly treatment was less protective. In these mice hypertrophy of colonic patches was seen after induction of colitis. We conclude that Th2-type colitis is dependent upon the presence of colonic patches. The effect of LTbetaR-Ig was mediated through prevention of colonic patch hypertrophy in the absence of IFN-gamma. Thus, LTbetaR-Ig may offer a possible treatment for the Th2-dominant form of colitis.

U.S. Army MEDEVAC in the new millennium: a medical perspective.

The U.S. Army Aeromedical Evacuation community (MEDEVAC) possesses a long-standing tradition of excellence in the care and transportation of combat casualties. Recent developments in civilian air medical transport and quantitative review of MEDEVAC operations have identified potential areas for improvement, concentrating on enhanced flight medic standards, training, sustainment and medical oversight of the air ambulance system. These proposed changes are discussed in detail, from the perspective of current emergency medicine and aviation medicine standards of practice. If instituted, these changes would facilitate the emergence of a true air medical transport capability comparable with the civilian community standard.

T cell receptor dynamism of mucosal and systemic CD4+ T cells in the course of an immune response to Escherichia coli heat-labile enterotoxin.

The changes in T cell receptor (TCR) Vbeta expression, use, and clonality in mice orally challenged with Escherichia coli heat-labile enterotoxin (LT) were assessed. Use of the TCR Vbeta family and clonality were significantly changed at the single-cell level. In Peyer's patches of treated mice, use of TCR Vbeta6, Vbeta8, and Vbeta14 increased in CD4(+)CD44(+) T cells, compared with use in nontreated mice. On the other hand, use of TCR Vbeta1 and Vbeta8 was enhanced in splenic CD4(+)CD44(+) T cells. Intraepithelial lymphocytes isolated from LT-challenged mice showed expanded clonality (e.g., Vbeta1, Vbeta2, Vbeta9, and Vbeta18) and altered TCR Vbeta use (e.g., Vbeta15, Vbeta16, and Vbeta17). These findings reveal that oral administration of LT has distinct effects on mucosal versus systemic alphabeta T cells for induction of CD4(+) T cells with selected Vbeta use. This most likely reflects the function of LT as a mucosal modulator.

A clinical inflammatory syndrome attributable to aerosolized lipid-DNA administration in cystic fibrosis.

Immunologic reactivity to lipid-DNA conjugates has traditionally been viewed as less of an issue than with viral vectors. We performed a dose escalation safety trial of aerosolized cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the lower airways of eight adult cystic fibrosis patients, and monitored expression by RT-PCR. The cDNA was complexed to a cationic lipid amphiphile (GL-67) consisting of a cholesterol anchor linked to a spermine head group. CFTR transgene was detected in three patients at 2-7 days after gene administration. Four of the eight patients developed a pronounced clinical syndrome of fever (maximum of 103.3EF), myalgias, and arthralgia beginning within 6 hr of gene administration. Serum IL-6 but not levels of IL-8, IL-1, TNF-alpha, or IFN-gamma became elevated within 1-3 hr of gene administration. No antibodies to the cationic liposome or plasmid DNA were detected. We found that plasmid DNA by itself elicited minimal proliferation of peripheral blood mononuclear cells taken from study patients, but led to brisk immune cell proliferation when complexed to a cationic lipid. Lipid and DNA were synergistic in causing this response. Cellular proliferation was also seen with eukaryotic DNA, suggesting that at least part of the immunologic response to lipid-DNA conjugates is independent of unmethylated (E. coli-derived) CpG sequences that have previously been associated with innate inflammatory changes in the lung.

Production of a recombinant hybrid molecule of cholera toxin-B-subunit and proteolipid-protein-peptide for the treatment of experimental encephalomyelitis.

Mucosal administration of experimental autoimmune encephalomyelitis (EAE)-specific autoantigens can reduce the onset of disease. To examine whether cholera toxin-B-subunit (CTB)-conjugated EAE-specific T-cell epitope can reduce development of the autoimmune disease in mice, we produced a recombinant hybrid molecule of CTB fusion protein linked with proteolipid-protein (PLP)-peptide139-151(C140S) at levels up to 0.1 gram per liter culture media in Bacillus brevis as a secretion-expression system. Amino acid sequencing and GM1-receptor binding assay showed that this expression system produced a uniformed recombinant hybrid protein. EAE was induced in SJL/J mice by systemic administration with the PLP-peptide. When nasally immunized 5 times with 70 microg rCTB PLP-peptide hybrid protein, mice showed a significantly suppressed development of ongoing EAE and an inhibition of both the PLP-peptide-specific delayed-type hypersensitivity (DTH) responses and leukocyte infiltration into the spinal cord. In contrast, all mice given the PLP-peptide alone or the PLP-peptide with the free form of CTB did not suppress the development of EAE and DTH responses. These results suggest that nasal treatment with the recombinant B. brevis-derived hybrid protein of CTB and autoantigen peptide could prove useful in the control of multiple sclerosis.

Safety and predictability of laser in situ keratomileusis enhancement by flap reelevation in high myopia.

PURPOSE: To evaluate the safety and predictability of laser in situ keratomileusis (LASIK) retreatment following primary procedures for high myopia and astigmatism. SETTING: Corneal Diseases and Excimer Laser Research Unit, Department of Ophthalmology, University of Dundee, Dundee, United Kingdom. METHODS: This prospective observational study of retreatment comprised a cohort of 109 eyes having primary LASIK for high myopia and astigmatism with a spherical equivalent (SE) of -9.70 diopters (D) +/- 4.06 (SD). Twenty-four eyes (22%) with an initial myopic SE of -9.83 +/- 3.50 D, a comparable subset of the entire group (P < .05), had retreatment for residual myopia (-3.02 +/- 2.17 D) to improve uncorrected visual acuity (UCVA) by reelevating the corneal flap and ablating the stromal bed. RESULTS: The mean follow-up after retreatment was 12.8 +/- 5.1 months (range 1.5 to 24 months; 19 eyes >/=6 months, 13 eyes > or = 12 months). The mean myopic SE was reduced to +0.53 +/- 0.62 D at 1 week, +0.05 +/- 0.50 D at 1 month, +0.30 +/- 0.50 D at 6 months, and +0.18 +/- 0.42 D at the latest follow-up, 12.8 months. At the latest review, 62% of eyes were within +/-0.50 D of emmetropia and 100% were within +/-1.00 D. The mean refraction did not alter statistically between 1 week and subsequent times. The mean UCVA improved from 6/30 prior to retreatment to 6/9 at the latest follow-up. Uncorrected visual acuity of 6/6 or better, 6/9 or better, and 6/12 or better was achieved by 33.0%, 75.0%, and 95.8% of eyes, respectively. No significant complications that led to a loss of best corrected visual acuity were encountered, although retreatment procedures were more uncomfortable than primary procedures and self-limiting; epithelial ingrowth that did not threaten vision was common, and 2 patients complained of nighttime visual symptoms. CONCLUSIONS: Retreatment of residual myopia by reelevating the flap was relatively safe and predictable, with a low risk of sight-threatening complications. However, longer term studies may be required to detect late complications.