Removal of orbital apex hemangioma using new transorbital craniotomy through suprabrow approach.

PURPOSE: To describe a technique combining the expertise of the oculoplastic orbital surgeon and the neurosurgeon which allows access to the posterior orbit, anterior fossa, cavernous sinus and suprasellar region with minimal brain manipulation. METHODS: A transorbital craniotomy through a suprabrow incision is performed removing part of the frontal bone and orbital roof as a single piece. This allows wide access with only minimal, if any, brain retraction. The superior, lateral and medial orbit is clearly visualized, as well as the apex of the orbit. The bone flap is replaced at the end of the case with Tantalum plates. RESULTS: A cavernous hemangioma at the orbital apex was removed without complications. The exposure was superb and allowed identification and preservation of orbital structures. CONCLUSIONS: Transorbital craniotomy allows for wide access to the posterior orbit and parasellar region and anterior fossa of the brain with minimal brain manipulation. The use of a suprabrow incision results in an excellent cosmetic result. There is minimal postoperative morbidity, which decreases hospitalization time.     

Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial

OBJECTIVE

To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN).

RESEARCH DESIGN AND METHODS

In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs).

RESULTS

Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%).

CONCLUSIONS

Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.Diabetic distal symmetric sensorimotor polyneuropathy (DSPN) is a chronic progressive disease affecting around one-third of the diabetic population and accounts for considerable morbidity, increased mortality, and reduced quality of life (1,2). Recent long-term studies in type 2 diabetic patients indicate that the current strategies of intensive diabetes therapy or multifactorial cardiovascular risk intervention are not sufficient to slow the progression of DSPN (3–5). Thus, effective treatment of DSPN remains challenging for the physician (1,6).Based on the pathogenetic mechanisms of DSPN, potential disease-modifying therapeutic approaches have been developed including antioxidants such as α-lipoic acid (ALA) (7–9) to diminish increased oxidative stress (10). Other potential modalities include the aldose reductase inhibitors (11), growth factors (12), and the protein kinase C-β inhibitor ruboxistaurin (13). These drugs have been designed to favorably influence the underlying pathophysiology of the disorder rather than for symptomatic pain relief. However, several problems have been encountered previously in designing appropriate clinical trials in DSPN. Among these, the most important are as follows: 1) the lack of homogeneity of patients studied with respect to both the form of neuropathy and the degree of glycemic control; 2) different pathogenetic pathways, the relative importance of which may vary intraindividually; 3) stages of neuropathy that are too advanced; 4) the use of end points with rather large variability between individuals and between centers; 5) the unknown relevance of end points used; and 6) study durations too short to allow for a favorable functional or structural effect (6,14,15).Treatment with ALA administered intravenously or orally for several weeks or months improves neuropathic symptoms and deficits (7–9). However, based on the assumption that a therapeutic agent may prevent worsening of DSPN but not cause improvement, clinical trials should be conducted for a minimum period of 3 years to achieve a clinically meaningful change of two Neuropathy Impairment Score (NIS) points (16,17). Therefore, we assessed the efficacy and safety of oral treatment with 600 mg ALA once daily in mild-to-moderate DSPN.     

Human CD8+ T cells do not require the polarization of lipid rafts for activation and proliferation

Lipid rafts are important signaling platforms in T cells. Little is known about their properties in human CD8(+) T cells. We studied polarization of lipid rafts by digital immunofluorescence microscopy in primary human T cells, using beads coated with anti-CD3 and anti-CD28 mAbs (CD3/28 beads). Unlike CD4(+) T cells, CD8(+) T cells did not polarize lipid rafts when stimulated with CD3/28 beads, when the anti-CD28 antibody was substituted with B7.2Ig, or if an anti-CD8 antibody was added to the CD3/28 beads. This phenomenon was also observed in human antigen-specific CD8(+) T cells. On stimulation with CD3/28 beads, the T cell antigen receptor clustered at the cell/bead contact area in both CD4(+) and CD8(+) T cells. Examination of lipid rafts isolated by sucrose density gradient centrifugation revealed the constitutive expression of p(56)Lck in the raft fractions of unstimulated CD8(+) T cells, whereas p(56)Lck was recruited to the raft fraction of CD4(+) T cells only after stimulation with CD3/28 beads. Stimulation with CD3/28 beads induced marked calcium flux, recruitment of PKC-theta and F-actin to the cell/bead contact site, and similar proliferation patterns in CD4(+) and CD8(+) T cells. Thus, polarization of lipid rafts is not essential for early signal transduction events or proliferation of human CD8(+) lymphocytes. It is possible that the lower stringency of CD8(+) T cell activation obviates a requirement for raft polarization.     

Importance of phosphoinositide 3-kinase gamma in the host defense against pneumococcal infection

RATIONALE: The pivotal role of phosphoinositide 3-kinase gamma (PI3Kgamma) in leukocyte recruitment makes it an attractive target for immunomodulatory therapy. However, interfering with PI3Kgamma signaling might increase the risk of bacterial infections in humans. OBJECTIVES: We hypothesized that deletion or pharmacologic inhibition of PI3Kgamma would impair the lung inflammatory response to the prototypic gram-positive bacterial pathogen Streptococcus pneumoniae. METHODS: PI3Kgamma knockout (KO) and wild-type mice were infected with S. pneumoniae or challenged with the pneumococcal virulence factor pneumolysin (PLY), and inflammatory leukocyte recruitment, bacterial pathogen elimination, and resolution/repair processes were determined. MEASUREMENTS AND MAIN RESULTS: PI3Kgamma KO mice challenged with PLY responded with lung edema and neutrophilic alveolitis, but showed a drop in alveolar macrophages and failed to recruit exudate macrophages when compared with wild-type mice. S. pneumoniae-infected PI3Kgamma KO mice and wild-type mice pretreated with the pharmacologic inhibitor AS-605240 recruited similar numbers of neutrophils but substantially fewer exudate macrophages into their lungs than control animals. They also displayed a significantly reduced lung pneumococcal clearance and showed an impaired resolution/repair process, leading to progressive pneumococcal pneumonia. CONCLUSIONS: PI3Kgamma gene deletion or pharmacologic inhibition of PI3Kgamma leads to perturbations of critical innate immune responses of the lung to challenge with S. pneumoniae. These data are of clinical relevance for the treatment of chronic inflammatory diseases where pharmacologic inhibition of PI3Kgamma signaling to attenuate effector cell recruitment may have implications for innate immune surveillance of remote organ systems.     

Clinical evaluation of the peak inspiratory flow generated by asthmatic children through the Novolizer

STUDY OBJECTIVE: To assess whether asthmatic children may generate sufficient peak inspiratory flow through the Novolizer, a novel multiple dose dry powder inhaler with acoustic and optical feedback mechanisms for correct inhalation. PATIENTS AND METHODS: 137 children (median age 7 years, range 4-2) with mild to moderate persistent asthma (FEV1 < 90% predicted or pre-treated with low-dose steroids) participated in this open, multi-centre study. After assessment of FEV1 and peak inspiratory flow (without inhalator device, PIF), the children were instructed to inhale with the Novolizer (PIF through inhaler, PIF-N). All assessments were done in triplicate and the mean out of three attempts analysed. RESULTS: Mean PIF was 128 +/- 61 l/min and mean PIF-N was 69 +/- 18 l/min. This is distinctly above the rate necessary to overcome the Novolizer's trigger threshold. PIF performance through the Novolizer was linear in the age interval of 4-8 years, no further increase was observed beyond 8 years. CONCLUSIONS: The medium to low intrinsic resistance of the Novolizer permits a relatively high PIF through this device. Together with the feedback mechanisms, this makes the Novolizer particularly valuable for inhalation therapy in asthmatic children with drugs such as salbutamol, formoterol, or budesonide.     

Dunaimycins, a new complex of spiroketal 24-membered macrolides with immunosuppressive activity. I. Taxonomy of the producing organisms, fermentation and antimicrobial activity.

The dunaimycins are a new complex of spiroketal 24-membered macrolides discovered in the fermentation broth of two actinomycetes. Based on taxonomic studies these two cultures, which were isolated from soil, were identified as Streptomyces diastatochromogenes strains AB 1691Q-321 and AB 1711J-452. The dunaimycins possess both immunosuppressive and antimicrobial activity.