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Rheumatoid arthritis (RA) is a prevalent systemic disease that causes significant joint dysfunction and disability. Dramatic improvements in the management of RA have been achieved with the use of biologic therapies aimed at cytokines, and B and T lymphocytes. Abatacept, a soluble receptor-IgG fusion protein that interferes with T-cell co-stimulation, has now been shown to improve symptoms, signs and function in RA, while also slowing radiographic progression. The degree of improvement in these measures is comparable to that seen with other biologic agents.Abatacept is effective in a range of RA patients that are encountered in clinical practice, namely methotrexate-inadequate responders, as well patients with inadequate responses to tumor necrosis factor inhibitors and patients with co-morbidities common in an aging population. When used for up to 2 years, abatacept appears to be safe and remains efficacious, although there is a trend toward increased infection rates when used in combination with other biologic therapies, as well as a trend toward more adverse events when used in a background of chronic obstructive pulmonary disease. Backed by these data, ongoing extensions of these trials, and additional new studies, abatacept represents the first co-stimulation modulator approved for RA, and is a welcome addition to the biologic therapies available for the management of this disease.

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ADP-ribosylation factor (Arf) 6 regulates the movement of membrane between the plasma membrane (PM) and a nonclathrin-derived endosomal compartment and activates phosphatidylinositol 4-phosphate 5-kinase (PIP 5-kinase), an enzyme that generates phosphatidylinositol 4,5-bisphosphate (PIP2). Here, we show that PIP2 visualized by expressing a fusion protein of the pleckstrin homology domain from PLCdelta and green fluorescent protein (PH-GFP), colocalized with Arf6 at the PM and on tubular endosomal structures. Activation of Arf6 by expression of its exchange factor EFA6 stimulated protrusion formation, the uptake of PM into macropinosomes enriched in PIP2, and recycling of this membrane back to the PM. By contrast, expression of Arf6 Q67L, a GTP hydrolysis-resistant mutant, induced the formation of PIP2-positive actin-coated vacuoles that were unable to recycle membrane back to the PM. PM proteins, such as beta1-integrin, plakoglobin, and major histocompatibility complex class I, that normally traffic through the Arf6 endosomal compartment became trapped in this vacuolar compartment. Overexpression of human PIP 5-kinase alpha mimicked the effects seen with Arf6 Q67L. These results demonstrate that PIP 5-kinase activity and PIP2 turnover controlled by activation and inactivation of Arf6 is critical for trafficking through the Arf6 PM-endosomal recycling pathway.

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Phosphoinositides such as phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate promote cell survival and protect against apoptosis by activating Akt/PKB, which phosphorylates components of the apoptotic machinery. We now report that another phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PIP2) is a direct inhibitor of initiator caspases 8 and 9, and their common effector caspase 3. PIP2 inhibited procaspase 9 processing in cell extracts and in a reconstituted procaspase 9/Apaf1 apoptosome system. It inhibited purified caspase 3 and 8 activity, at physiologically attainable PIP2 levels in mixed lipid vesicles. Caspase 3 binding to PIP2 was confirmed by cosedimentation with mixed lipid vesicles. Overexpression of phosphatidylinositol phosphate 5-kinase alpha (PIP5KIalpha), which synthesizes PIP2, suppressed apoptosis, whereas a kinase-deficient mutant did not. Protection by the wild-type PIP5KIalpha was accompanied by decreases in the generation of activated caspases and of caspase 3-cleaved PARP. Protection was not mediated through PIP3 or Akt activation. An anti-apoptotic role for PIP(2) is further substantiated by our finding that PIP5KIalpha was cleaved by caspase 3 during apoptosis, and cleavage inactivated PIP5KIalpha in vitro. Mutation of the P(4) position (D279A) of the PIP5KIalpha caspase 3 cleavage consensus prevented cleavage in vitro, and during apoptosis in vivo. Significantly, the caspase 3-resistant PIP5KIalpha mutant was more effective in suppressing apoptosis than the wild-type kinase. These results show that PIP2 is a direct regulator of apical and effector caspases in the death receptor and mitochondrial pathways, and that PIP5KIalpha inactivation contributes to the progression of apoptosis. This novel feedforward amplification mechanism for maintaining the balance between life and death of a cell works through phosphoinositide regulation of caspases and caspase regulation of phosphoinositide synthesis.

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Many management approaches have been considered to relieve upper respiratory obstruction in patients with Pierre Robin sequence, but the choice of treatment is determined by the severity of the obstruction. These options include prone positioning, the use of a nasal trumpet, and surgery. One surgical technique is the subperiosteal release of the floor of the mouth musculature. The theory behind this procedure is that this musculature is under tension, and therefore it pushes the tongue upward and backward, resulting in respiratory obstruction. In theory, the release of this musculature from the mandible should alleviate the tension and hence clear the obstruction. In an attempt to objectively evaluate this theory, we performed subperiosteal release surgery on two infants. Our first patient required an emergent tracheostomy on postoperative day 2 because of the onset of surgically induced airway edema. To avoid this complication in the second patient, we performed a tracheostomy at the same time as surgery. Pre- and postoperative magnetic resonance imaging in the second patient revealed only a minimal change in the anatomy of the floor of the mouth musculature. We believe the subperiosteal release of the floor of the mouth musculature requires further evaluation before it can be considered to be effective in the surgical treatment of respiratory obstruction in Pierre Robin sequence.

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BACKGROUND: Phosphatidylinositol 4,5-bisphosphate (PIP(2)) has been implicated in the regulation of the actin cytoskeleton and vesicle trafficking. It stimulates de novo actin polymerization by activating the pathway involving the Wiskott-Aldrich syndrome protein (WASP) and the actin-related protein complex Arp2/3. Other studies show that actin polymerizes from cholesterol-sphingolipid-rich membrane microdomains called 'rafts', in a manner dependent on tyrosine phosphorylation. Although actin has been implicated in vesicle trafficking, and rafts are sites of active phosphoinositide and tyrosine kinase signaling that mediate apically directed vesicle trafficking, it is not known whether phosphoinositide regulation of actin dynamics occurs in rafts, or if it is linked to vesicle movements. RESULTS: Overexpression of type I phosphatidylinositol phosphate 5-kinase (PIP5KI), which synthesizes PIP(2), promoted actin polymerization from membrane-bound vesicles to form motile actin comets. Pervanadate (PV), a tyrosine phosphatase inhibitor, induced comets even in the absence of PIP5KI overexpression. PV increased PIP(2) levels, suggesting that it induces comets by changing PIP(2) homeostasis and by increasing tyrosine phosphorylation. Platelet-derived growth factor (PDGF) enhanced PV-induced comet formation, and these stimuli together potentiated the PIP5KI effect. The vesicles at the heads of comets were enriched in PIP5KIs and tyrosine phosphoproteins. WASP-Arp2/3 involvement was established using dominant-negative WASP constructs. Endocytic and exocytic markers identified vesicles enriched in lipid rafts as preferential sites of comet generation. Extraction of cholesterol with methyl-beta-cyclodextrin reduced comets, establishing that rafts promote comet formation. CONCLUSIONS: Sphingolipid-cholesterol rafts are preferred platforms for membrane-linked actin polymerization. This is mediated by in situ PIP(2) synthesis and tyrosine kinase signaling through the WASP-Arp2/3 pathway. Actin comets may provide a novel mechanism for raft-dependent vesicle transport and apical membrane trafficking.

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The purpose of this investigation was to evaluate the ability of palatal lift prostheses to stimulate the neuromuscular activity of the velopharynx. Nasendoscopic evaluations were audio-videotaped preprosthetic and postprosthetic management for 25 patients who underwent placement of a palatal lift prosthesis for velopharyngeal dysfunction (VPD). These audio-videotapes were presented in blinded fashion and random order to three speech pathologists experienced in assessment of patients with VPD. They rated the tapes on the following parameters: VP gap size, closure pattern, orifice estimate, direction and magnitude of change, and qualitative descriptions of the adequacy of VP closure during speech. VP closure for speech was unchanged in 69% of patients and the number of patients rated as improved or deteriorated was nearly identical at about 15%. Postintervention gap shape remained unchanged in 70% of patients. The extent of VP orifice closure during speech remained unchanged in 57% of patients. Articulations that could impair VP function improved in 30% of patients, deteriorating in only 4%. Results of this study neither support the concept that palatal lift prostheses alter the neuromuscular patterning of the velopharynx, nor provide objective documentation of the feasibility of prosthetic reduction for weaning.

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Rats were given intracerebroventricular injections of either angiotensin II (ANG II) or the cholinomimetic carbachol. Some rats received cotreatment with ANG II antagonists selective for either angiotensin receptor AT1 (losartan) or AT2 (PD-123319, CGP-42112A). One hour later, the rats were killed and the brains processed for immunocytochemical detection of Fos-like immunoreactivity (FLI). ANG II treatment induced strong FLI in the anterior subfornical organ (SFO), median preoptic nucleus (MnPO), organum vasculosum laminae terminalis (OVLT), and supraoptic and paraventricular hypothalamic nuclei (SON, PVH). The AT1 antagonist abolished FLI in all regions normally stimulated by ANG II. The AT2 antagonist PD-123319 reduced FLI in SON and PVH, but CGP-42112A was less effective. Carbachol induced strong FLI in SON, PVH, and MnPO and only moderate FLI in SFO and OVLT. The AT1 antagonist prevented carbachol-induced FLI in the MnPO only. The distributions of FLI are compared between these central dipsogens and with that previously reported after peripheral infusion of ANG II, and their implications for mapping central thirst pathways are discussed.

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Immediate early genes, detected by Fos- and Jun-like immunoreactivity (FLI, JLI), were induced in discrete regions of the rat brain by intravenous infusion of angiotensin II (Ang II) at dipsogenic doses. The regions included subfornical organ (SFO), organum vasculosum laminae terminalis (OVLT), median preoptic nucleus (MnPO), supraoptic nucleus (SON), and the magnocellular part of the paraventricular hypothalamus (PVH). These responses were sustained for up to 6 h of infusion. In SFO, FLI was induced preferentially in the posterior part, while JLI occurred in more central regions. Cerebroventricular (ICV) injection of the Ang II type 1 receptor (AT-1) antagonist, losartan potassium, completely prevented the FLI induced by Ang II in these brain regions. ICV injection of the Ang II type 2 receptor (AT-2) antagonist, PD 123319, did not reduce Ang II-induced FLI in SFO, OVLT and MnPO, but markedly attenuated the activation in SON and PVH. To determine whether SFO is the primary site for transduction of the circulating Ang II signal, electrolytic lesions were made in or rostral to the SFO. Rats with complete lesions showed a complete absence of Ang-induced FLI in SON and PVH. The data are discussed in terms of functional mapping of the brain regions activated by circulating Ang II and neural circuitry for water intake, including the possible role of AT-2 receptors in PVH and SON.

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Nonpeptide angiotensin AT-1 and AT-2 receptor antagonists were administered cerebroventricularly to rats and their effects on various types of angiotensin II (AII)-stimulated water and NaCl intakes examined. The AT-1 receptor blocker, losartan potassium (DUP 753), inhibited water intake evoked by central administration of AII, with the 50% inhibitory dose being less than 0.1 microgram. The functional inhibition by higher doses lasted at least 1 h. The AT-2 receptor antagonist PD 123319 also inhibited AII-induced water intake, but at doses about tenfold higher than losartan. Central, but not peripheral, administration of losartan partially inhibited NaCl intake induced by either sodium depletion, treatment with angiotensin converting enzyme inhibitors (CEIs), or adrenalectomy. PD 123319 partially inhibited NaCl intake induced by both sodium depletion and administration of CEI, but not after adrenalectomy. Another AT-2 receptor antagonist, CGP 42112A, likewise inhibited NaCl intake after sodium deprivation. These data suggest that both AT-1 and AT-2 receptor subtypes in the brain are involved in angiotensin-related water and NaCl intakes.

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We report a case of spontaneous mediastinal haematoma. This unusual clinical entity, though uncommon, must be considered in any patient presenting with the typical triad of symptoms of acute superior mediastinal compression, widening of the superior mediastinum on chest radiographs, bruises on the neck appearing within 48 hours of exertion, sneezing, coughing or vomiting. The signs observed with computed tomography in mediastinal haemorrhage are described. The exact source of the haemorrhage remains unknown despite careful radiological investigation and thoracotomy.

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The authors describes a case of Menkes' disease, sex-linked recessive hereditary disease characterized by early progressive psychomotor deterioration, failure to gain weight, seizures, hypothermie and characteristic Kinky hair (Pilitorti). This boy is a blind child, unable to fix and follow light. Fundus examination shows optic nerve atrophy with tortuosity of the retinal blood vessels. The case is discussed in the light of similar and others reports in the literature. The disease is believed to be cause by a generalized copper deficiency in the body by defect in copper intestinal absorbtion. The pathologic changes in the retina are similar to those seen in the brain which shows diffuse neuronal degeneration lose of nerve filers and optic atrophy. Retinal changes should be reversible by short term systemic copper administration.

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