A prospective algorithm for the management of air leaks after pulmonary resection

BACKGROUND: Air leaks (ALs) are a common complication after pulmonary resection, yet there is no consensus on their management. METHODS: An algorithm for the management of chest tubes (CT) and ALs was applied prospectively to 101 consecutive patients who underwent elective pulmonary resection. Air leaks were graded daily as forced expiratory only, expiratory only, inspiratory only, or continuous. All CTs were kept on 20 cm of suction until postoperative day 2 and were then converted to water seal. On postoperative day 3, if both a pneumothorax and AL were present, the CT was placed to 10 cm H2O of suction. If a pneumothorax was present without an AL, the CT was returned to 20 cm H2O of suction. Air leaks that persisted after postoperative day 7 were treated with talc slurry. RESULTS: There were 101 patients (67 men); on postoperative day 1, 26 had ALs and all were expiratory only. Univariable analysis showed a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) (p = 0.005), increased age (p = 0.007), increased ratio of residual volume to total lung capacity (RV/TLC) (p = 0.04), increased RV (p = 0.02), and an increased functional residual capacity (FRC) (p = 0.02) to predict the presence of an AL on postoperative day 1. By postoperative day 2, 22 patients had expiratory ALs. After 12 hours of water seal, 13 of the 22 patients' ALs had stopped, and 3 more sealed by the morning of postoperative day 3. However, 2 of the 6 patients whose ALs continued experienced a pneumothorax. Five of the 6 patients with ALs on postoperative day 4 still had ALs on postoperative day 7, and all were treated by talc slurry through the CT. All ALs resolved within 24 hours after talc slurry. CONCLUSIONS: Most ALs after pulmonary resection are expiratory only. A low FEV1/FVC ratio, increased age, increased RV/TLC ratio, increased RV, and an increased FRC were predictors of having an ALs on postoperative day 1. Conversion from suction to water seal is an effective way of sealing expiratory AL, and pneumothorax is rare. If an expiratory AL does not stop by postoperative day 4 it will probably persist until postoperative day 7, and talc slurry may be an effective treatment.     

ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterization

The antinociceptive effects of ABT-594, a novel nicotinic acetylcholine receptor (nAChR) ligand, were examined in rats in models of acute thermal (hot box) and persistent chemical (formalin test) pain. Also, the effects of ABT-594 treatment on motor function and electroencephalogram (EEG) were determined. In the hot box and formalin test (i.e., phase 1 and 2), acute treatment with ABT-594 (0.03, 0.1 and 0.3 mumol/kg i.p.) produced significant dose-dependent antinociceptive effects. In the hot box, the efficacy of ABT-594 was maintained after a repeated dosing paradigm (5 days b.i.d.i.p.). ABT-594 was fully efficacious in the formalin test when administered before formalin, and also retained significant efficacy (0.3 mumol/kg i.p.) when administered after formalin injection. The antinociceptive effects of ABT-594 in the hot box and formalin tests were attenuated by pretreatment with the nAChR antagonist, mecamylamine, and in animals treated with the nAChR antagonist chlorisondamine, given centrally (10 micrograms/rat i.c.v. 5 days before), but not in animals pretreated with the opioid receptor antagonist, naltrexone. Acute treatment with ABT-594 produced an initial decrease in open-field locomotor activity, which was absent in animals dosed repeatedly (5 days b.i.d.) with ABT-594. Also, acute treatment with ABT-594 decreased body temperature and decreased the amount of time the animals could maintain balance in an edge-balance test. These effects were no longer present in animals dosed repeatedly with ABT-594. At antinociceptive doses, ABT-594 produced activation of free running EEG in contrast to the sedative-like effects of morphine. Full antinociceptive efficacy was maintained in both the hot box and formalin tests after oral administration, whereas the effects on motoric performance were attenuated. In conclusion, these data demonstrate that ABT-594 is a potent antinociceptive agent with full efficacy in models of acute and persistent pain and that these effects are mediated predominately by an action at central neuronal nAChRs. In addition, antinociceptive effects were maintained after repeated dosing, whereas effects of ABT-594 on motor and temperature measures were attenuated in animals treated repeatedly with ABT-594. Thus, compounds acting at nAChRs may represent a novel approach for the treatment of a variety of pain states.     

Diagnostic rules for children with PDD-NOS and multiple complex developmental disorder

This study was designed to examine the classification performance of diagnostic rules for pervasive developmental disorder not otherwise specified (PDD-NOS) and multiple complex developmental disorder (McDD), with clinical diagnosis as the gold standard. McDD is an heuristic concept of a developmental disorder characterised by social impairments, affective dysregulation, and thought disturbance. Detailed information on the symptoms, reliably extracted from the charts of 103 children with PDD-NOS and McDD, 32 with autistic disorder, and 96 with non-PDD disorders, was used to determine the presence of the DSM-IV criteria of autistic disorder and the criteria of McDD. A scoring rule for PDD-NOS based on a short set of seven DSM-IV criteria with a cut-off point of three items and one social interaction item set as mandatory had the best balance between high sensitivity and high specificity. The most effective and simple rule based on McDD criteria had a cut-off of three items, out of six items of anxieties and thought disturbance.     

A double-masked, randomized, 1-year study comparing the corneal effects of dorzolamide, timolol, and betaxolol. Dorzolamide Corneal Effects Study Group

OBJECTIVE: To compare the long-term effects of dorzolamide hydrochloride (Trusopt, Merck and Co Inc, White-house Station, NJ), timolol maleate, and betaxolol hydrochloride on corneal endothelial cell density and corneal thickness. METHODS: This 1-year multicenter study was conducted in 298 patients with ocular hypertension or open-angle glaucoma who had a baseline central corneal endothelial cell density greater than 1500 cells/mm2 and central corneal thickness less than 0.68 mm in each eye. Patients were randomized to 0.5% betaxolol twice daily, 0.5% timolol twice daily, or 2.0% dorzolamide 3 times daily. Specular microscopy and ultrasonic pachymetry of the central cornea was performed at baseline and 6 and 12 months following institution of therapy. Endothelial cell densities were determined by a single masked observer. RESULTS: The mean percent changes from baseline for both outcome measures were similar in all 3 treatment groups at both 6 and 12 months. After 1 year of treatment, the mean percent loss in endothelial cell density from baseline was 3.6%, 4.5%, and 4.2% for the dorzolamide, timolol, and betaxolol groups, respectively. The mean percent change from baseline for corneal thickness was 0.47%, -0.25%, and 0.39% for the dorzolamide, timolol, and betaxolol groups, respectively. CONCLUSIONS: Dorzolamide is equivalent to timolol and betaxolol in terms of the change in central endothelial cell density and thickness after 1 year of therapy. All 3 treatments exhibit good long-term corneal tolerability in patients with normal corneas at baseline.     

Antineoplastic agents 365. Dolastatin 10 SAR probes

The remarkable anticancer drug dolastatin 10 (1a) from the Indian Ocean sea hare Dolabella auricularia is currently undergoing phase I clinical trials. Thirty-eight new structural modifications of this unusual peptide have been synthesized and evaluated against a variety of human and murine cancer cell lines, and for their ability to inhibit tubulin polymerization and vinblastine and GTP binding to tubulin. Dolastatin 10 and one structural modification was found to have antifungal activity, while one other structural modification of the parent compound exhibited antibacterial activity. Some of the new peptides approximated the antineoplastic potency of dolastatin 10, especially those based on replacement of the Doe unit with Met, Phe or an appropriately substituted phenylethylamide.     

Hippocampal AMPA and NMDA mRNA levels correlate with aberrant fascia dentata mossy fiber sprouting in the pilocarpine model of spontaneous limbic epilepsy

There is considerable controversy whether aberrant fascia dentata (FD) mossy fiber sprouting is an epiphenomena related to neuronal loss or a pathologic abnormality responsible for spontaneous limbic seizures. If mossy fiber sprouting contributes to seizures, then reorganized axon circuits should alter postsynaptic glutamate receptor properties. In the pilocarpine-status rat model, this study determined if changes in alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and n-methyl-D-aspartic acid (NMDA) receptor subunit mRNA levels correlated with mossy fiber sprouting. Sprague-Dawley rats were injected with pilocarpine (320 mg/kg; i.p.) and maintained in status epilepticus for 6 to 8 hours (pilocarpine-status). Rats were killed during the: (1) latent phase after neuronal loss but before spontaneous limbic seizures (day 11 poststatus; n = 7); (2) early seizure phase after their first seizures (day 25; n = 7); and (3) chronic seizure phase after many seizures (day 85; n = 9). Hippocampi were studied for neuron counts, inner molecular layer (IML) neo-Timm's staining, and GluR1-3 and NMDAR1-2b mRNA levels. Compared with controls, pilocarpine-status rats in the: (1) latent phase showed increased FD GluR3, NMDAR1, and NMDAR2b; greater CA4 and CA1 NMDAR1; and decreased subiculum GluR1 hybridization densities; (2) early seizure phase showed increased FD GluR3, increased CA1 NMDAR1, and decreased subiculum NMDAR2b densities; and (3) chronic seizure phase showed increased FD GluR2; increased FD and CA4 GluR3; decreased CA1 GluR2; and decreased subiculum GluR1, GluR2, NMDAR1, and NMDAR2b levels. In multivariate analyses, greater IML neo-Timm's staining: (1) positively correlated with FD GluR3 and NMDAR1 and (2) negatively correlated with CA1 and subiculum GluR1 and GluR2 mRNA levels. These results indicate that: (1) hippocampal AMPA and NMDA receptor subunit mRNA levels changed as rats progressed from the latent to chronic seizure phase and (2) certain subunit alterations correlated with mossy fiber sprouting. Our findings support the hypothesis that aberrant axon circuitry alters postsynaptic hippocampal glutamate receptor subunit stoichiometry; this may contribute to limbic epileptogenesis.     

Use of nonoxynol-9 and changes in vaginal lactobacilli

The conformation of lens crystallins in vivo or in a highly concentrated solution is not well established. Most studies were carried out in dilute solutions in which protein-protein interaction is minimal. In order to see whether there is conformational change (tertiary and secondary structures) when crystallin solutions are brought to high concentrations, we have performed the following molecular spectroscopic measurements: circular dichroism (CD) and Fourier transform infrared (FTIR). Near-UV CD measurements showed a more than two-fold increase in CD intensity (molar ellipticity) for the total water-soluble (WS) protein from young calf lens nucleus in a highly concentrated solution (> 300 mg/ml in a 0.01-mm cell), when compared with a dilute solution (1000-fold dilution in a 10-mm cell). The individual crystallins in concentrated solutions also showed an increase in CD intensity, but of different magnitude: alpha-crystallin > beta-crystallin > gamma-crystallin. The increased CD indicates that lens crystallins are in a more compact structure in highly concentrated solutions; they likely undergo a transition from a mobile to an immobile state. Change in near-UV CD usually is caused by restricted mobility of aromatic side groups, particularly Trp. The transition involves not only a change in protein tertiary and/or quaternary structure, but also in protein backbone structure. The change of protein backbone structure was drawn from FTIR measurements. FTIR spectra, sensitive to the secondary structure in the amide I region, could be measured for a highly concentrated solution for which far-UV CD measurement is not feasible. The secondary structure that showed prominent change for alpha-crystallin in a highly concentrated solution was beta-conformation: increase in beta-turn with a concomitant decrease of alpha-helix structure.     

Wound healing: a paradigm for lumen narrowing after arterial reconstruction

PURPOSE: The intimal hyperplasia hypothesis that equates lumen narrowing after arterial injury with intimal mass has recently been challenged. Evidence has emerged to suggest that lumen narrowing is caused in large part by changes in artery wall geometry rather than intimal mass per se. We have begun to explore this hypothesis in a unique nonhuman primate model of atherosclerosis. METHODS: Monkeys who were fed an atherogenic diet for 3 to 5 years underwent experimental angioplasty of the left iliac artery. The contralateral iliac artery served as an intraanimal control. Arteries were removed 2, 4, 7, 14, 28, or 112 days later for analysis (6 or 13 per time point). Angioplasty dilated arteries by fracturing atheroma and stretching or tearing the media. Cross-sections of injured arteries were analyzed for expression of extracellular matrix components and cell surface integrins that are important in wound healing. Antibodies, riboprobes, or histochemical stains specific for fibrin, hyaluronan, versican (chondroitin sulfate-containing proteoglycan), procollagen-I, elastin, and the alpha 2 beta 1 and alpha V beta 3 integrins were used. RESULTS: A thin mural thrombus was seen at sites of denudation and plaque fracture (days 2 to 7). This provisional matrix was invaded by leukocytes (days 2 to 4) and alpha-actin-positive smooth muscle cells (SMCs; days 4 to 7). Thrombus was replaced by SMCs expressing hyaluronan and the associated versican proteoglycans (day 14). Versican was expressed throughout the neointima as it enlarged (day 28), but expression later subsided (day 112). Procollagen-I expression initially increased in the adventitia (day 4) and then in the forming neointima (day 14). Procollagen-I expression was found to persist within the adventitia and in the neointima in SMCs nearest the lumen (days 28 to 112). Elastin staining was prominent within the mature neointima (day 112) but not at earlier time points. Integrin expression also increased within the injured artery wall. alpha v beta 3 staining (fibrin[ogen] receptor) increased in the injured media (days 2 to 7) and was then seen throughout the early neointima (day 7). Low level expression of alpha V beta 3 subsequently persisted within the forming neointima (day 28). alpha 2 beta 1 (collagen receptor) expression increased in the neointima in SMCs nearest the lumen (day 28). CONCLUSIONS: Lumen narrowing after angioplasty in this model of atherosclerosis is caused largely by decreased artery wall diameter. The pattern of matrix and integrin expression within the injured artery wall is in many ways analogous to that of healing wounds. These observations suggest that tissue contraction may play a role in lumen narrowing at sites of arterial reconstruction. Strategies to inhibit wound contraction may prove effective in preventing restenosis.     

The lunatic fringe gene is a target of the molecular clock linked to somite segmentation in avian embryos

The most obvious segments of the vertebrate embryo are the trunk mesodermal somites which give rise to the segmented vertebral column and the skeletal muscles of the body. Mechanistic insights into vertebrate somitogenesis have recently been gained from observations of rhythmic expression of the avian hairy-related gene (c-hairy1) in chick presomitic mesoderm (PSM), suggesting the existence of a molecular clock linked to somite segmentation ([1]; reviewed in [2]). Here, we show that lunatic Fringe (IFng), a vertebrate homolog of the Drosophila Fringe gene, is also expressed rhythmically in PSM. The PSM expression of IFng was observed as coordinated pulses of mRNA resembling the expression of c-hairy1. We show that c-hairy1 and IFng expression in the PSM are coincident, indicating that both genes are responding to the same segmentation clock. The genes were found to differ in their regulation, however; in contrast to c-hairy1, IFng mRNA oscillations required continued protein synthesis, suggesting that IFng could be acting downstream of c-hairy1 in the clock mechanism. In Drosophila, Fringe has been shown to play a role in modulating Notch-Delta signalling [3,4], a pathway which in vertebrates has been implicated in defining somite boundaries [5-9]. These observations place the segmentation clock upstream of the Notch-Delta pathway during vertebrate somitogenesis.