Severe bronchopulmonary dysplasia increases risk for later neurological and motor sequelae in preterm survivors

Preterm children who develop severe chronic lung disease may be developmentally compromised by exposure to hypoxic episodes. This study aims to determine if children with severe bronchopulmonary dysplasia (BPD) who required home oxygen therapy were at greater risk for neurological and motor deficits at school age than preterm peers without BPD. This study evaluated 27 subjects with BPD and 27 preterm control infants matched for gestational age, birthweight, sex, and year of birth at a mean age of 9.9 years (2.0 SD) using standardized neuromotor outcome measures. Pair-matched comparisons and regression analyses were used to determine if subjects with BPD were at increased risk for neuromotor sequelae. Neurological abnormalities, including subtle neurological signs, cerebral palsy, microcephaly, and behavioral difficulties were highly prevalent in the BPD group (71% compared with 19% in control group, P<0.005). Over half the BPD cohort had difficulties in gross and/or fine motor skills. There were significant differences in postural stability between groups. Duration of hospitalization and home oxygen treatment, and decreased lung function at school age, markers of severity of illness, correlated with motor outcomes. The findings underline the importance of preventing the cardiorespiratory complications associated with chronic lung disease to minimize disability in preterm children. For children with severe BPD, better recognition and subsequent remediation of neuromotor impairments that manifest at school age may help maximize their functional potential.     

Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization

OBJECTIVES: This study tested the hypothesis that a recombinant human C5a antagonist, CGS 32359, attenuates neutrophil activation and reduces infarct size in a porcine model of surgical revascularization. METHODS: CGS 32359 (0.16-16 micromol/L) dose-dependently inhibited superoxide production by human C5a-activated porcine neutrophils (18 +/- 3.7 vs 1.6 +/- 0.5 nmol/5 min/5 x 10(6) neutrophils; P <.05) and reduced neutrophil adherence to coronary endothelium from 194 +/- 9 to 43 +/- 6 neutrophils/mm(2) (P <.05). The left anterior descending coronary artery was occluded for 50 minutes, after which saline solution (n = 8), mannitol-buffer vehicle (n = 9, 102 mg/kg bolus, 102 mg. kg(-1). h(-1)), or CGS 32359 (CGS, n = 7, 60 mg/kg bolus, 60 mg. kg(-1). h(-1)) was infused. After ischemia, 1-hour arrest was achieved by means of multidose hypothermic (4 degrees C) blood cardioplegia, followed by 2.5 hours of off-bypass reperfusion. The ligature on the left anterior descending artery was released before the second infusion of cardioplegic solution. RESULTS: Area at risk was similar in all groups (saline solution, 27% +/- 2%; mannitol-buffer vehicle, 26% +/- 2%; CGS, 26% +/- 2% left ventricular mass). Infarct size (area necrosis/area at risk) was significantly reduced by CGS (18% +/- 6%, P <.05) versus saline solution (52% +/- 3%) and mannitol-buffer vehicle (60% +/- 4%). Postischemic systolic shortening (sonomicrometry) in the area at risk was significantly improved with CGS (0.8% +/- 0.9%) compared with saline solution (-3.7% +/- 1.1%) and mannitol-buffer vehicle (-6.4% +/- 1.0%). Myeloperoxidase activity from accumulated neutrophils was less in the ischemic zone of CGS (0.014 +/- 0.002 U/100 mg tissue; P <.05) than mannitol-buffer vehicle (0.133 +/- 0.012 U/100 mg tissue). CONCLUSIONS: We conclude that the recombinant human C5a receptor antagonist CGS 32359 inhibits surgical ischemia-reperfusion injury after coronary occlusion.     

Effects of hindlimb unloading on neuromuscular development of neonatal rats

We hypothesized that hindlimb suspension unloading of 8-day-old neonatal rats would disrupt the normal development of muscle fiber types and the motor innervation of the antigravity (weightbearing) soleus muscles but not extensor digitorum longus (EDL) muscles. Five rats were suspended 4.5 h and returned 1.5 h to the dam for nursing on a 24 h cycle for 9 days. To control for isolation from the dam, the remaining five littermates were removed on the same schedule but not suspended. Another litter of 10 rats housed in the same room provided a vivarium control. Fibers were typed by myofibrillar ATPase histochemistry and immunostaining for embryonic, slow, fast IIA and fast IIB isomyosins. The percentage of multiple innervation and the complexity of singly-innervated motor terminal endings were assessed in silver/cholinesterase stained sections. Unique to the soleus, unloading accelerated production of fast IIA myosin, delayed expression of slow myosin and retarded increases in standardized muscle weight and fiber size. Loss of multiple innervation was not delayed. However, fewer than normal motor nerve endings achieved complexity. Suspended rats continued unloaded hindlimb movements. These findings suggest that motor neurons resolve multiple innervation through nerve impulse activity, whereas the postsynaptic element (muscle fiber) controls endplate size, which regulates motor terminal arborization. Unexpectedly, in the EDL of unloaded rats, transition from embryonic to fast myosin expression was retarded. Suspension-related foot drop, which stretches and chronically loads EDL, may have prevented fast fiber differentiation. These results demonstrate that neuromuscular development of both weightbearing and non-weightbearing muscles in rats is dependent upon and modulated by hindlimb loading.     

Lumbar epidural morphine in humans and supraspinal analgesia to experimental heat pain

BACKGROUND: Epidural administration of morphine is a common analgesic technique to manage pain. Morphine spreads from the epidural space to the cerebrospinal fluid and then rostrally, causing side effects mediated by the brain stem. However, data on the rostral spread of morphine-mediated analgesia are sparse. This study examined the rostral spread of analgesic effects on heat and electrical pain after epidural administration of morphine. METHODS: In a randomized, double-blinded, placebo-controlled, crossover study, 5 mg morphine or saline placebo were injected into the lumbar epidural space in nine healthy volunteers. Correct needle placement was confirmed with fluoroscopy. Analgesia to experimental nociceptive heat and electrical stimuli was measured at lumbar (L4), thoracic (T10), cervical (C2), and trigeminal (V2) levels before and 2, 5, 10, and 24 h after epidural injection. Plasma samples for assaying morphine concentrations were drawn before and after each analgesic evaluation. RESULTS: Epidural morphine significantly attenuated experimental heat pain at all dermatomes tested compared with saline placebo. Analgesic effects were significant at L4 after 2, 5, and 10 h, at T10 after 5, 10, and 24 h, and at V2 after 10 h. Electrical pain was attenuated at the lumbar and thoracic but not at the cervical dermatome. Analgesic effects were significant at L4 after 2, 5, and 10 h and at T10 after 5 and 10 h. Morphine plasma concentrations were below the detection limit (1 ng/ml) in eight of the nine subjects 10 h after epidural injection. CONCLUSIONS: Lumbar epidural injection of morphine attenuated cutaneous heat pain up to the trigeminal dermatome during a 24-h observation period. In a clinical context, this implies that some types of pain may be attenuated up to the supraspinal level after lumbar epidural administration of morphine.     

The effects of sucrose on stability of human brain natriuretic peptide [hBNP (1–32)] and human parathyroid hormone [hPTH (1–34)]

Abstract: Although the effect of sucrose on the physical stability of proteins has been well documented, its impact on their chemical stability is largely unknown. The aim of this study was to investigate the potential effects of sucrose on the structural conformation of human brain natriuretic peptide [hBNP (1–32)] and the synthetic human parathyroid hormone [hPTH (1–34)], and link these effects to chemical degradation pathways of these peptides. The stability of hBNP (1–32) and hPTH (1–34) was studied at pH 5.5. Aggregation was monitored using size exclusion high‐performance liquid chromatography (SE‐HPLC), whereas oxidation and deamidation products were measured by reversed phase (RP) HPLC. Fourier transform infrared (FT‐IR) spectroscopy was used to study the peptides’ conformation. Sucrose retarded aggregation, deamidation, and oxidation of hBNP (1–32) and hPTH (1–34), with a maximum effect at relatively high concentrations (as much as 1 m ). FT‐IR spectroscopy indicated that sucrose maintained the native conformation of hBNP (1–32) and induced small conformation changes in the hPTH (1–34) structure. Sucrose enhanced the stability of hBNP (1–32) and hPTH (1–34) in liquid formulations. The stabilizing effect of sucrose was due to a large extent to retardation of oxidation and deamidation of hBNP (1–32) and hPTH (1–34).     

Analysis of vesicle fluid following the sting of the lionfish Pterois volitans

P. S. , H. E. , R. S. and J. P. . Analysis of vesicle fluid following the sting of the lionfish Pterois volitans. Toxicon 25, 1350 – 1353, 1987. — Fluid aspirated from blisters following a lionfish (Pterois volitans) sting was analyzed utilizing combined capillary column gas chromatography and negative ion chemical ionization mass spectrometry. Analysis for prostaglandin F₂ demonstrated 16.91 ng/ml, for prostaglandin E₂ 0.143 ng/ml, for 6-keto-prostaglandin F₁ less than 0.1 ng/ml (nondetectable) and for thromboxane B₂ 1.65 ng/ml. Platelet aggregation studies showed that blister fluid caused aggregation of isolated platelets only, which was inhibited by heat treatment or by the presence of normal donor plasma.     

Comparison of in vivo and in vitro percutaneous absorption of T-2 toxin in guinea pigs

The fate and distribution of T-2 were examined in 6 guinea pigs. T-2 (1.2 micrograms/cm2), in methanol or DMSO, was painted onto the shaved backs of guinea pigs, a screen barrier was applied, urine and feces were collected daily and the guinea pigs were killed after 48 hr. Disks of skin (lateral to the in vivo site of application) were excised from the guinea pigs and used for in vitro penetration studies with static diffusion cells. Skin excised from 6 additional guinea pigs was used for penetration studies with flow-through diffusion cells. For in vitro studies, T-2 dissolved in methanol or DMSO was applied to the epidermal surfaces and the appearance of penetrant in receptor fluid bathing the dermal surfaces was monitored for 48 hr. Metabolism of T-2 was measured by using thin layer radiochromatography to identify metabolites. In the in vivo study, mean cutaneous absorption (n = 3) after 48 hr (expressed as per cent dose) was 22.5 and 51.9 for the methanol and DMSO groups, respectively. In vitro cutaneous penetration for static diffusion cells was 3.9 and 38.4 for the methanol and DMSO groups. For flow-through diffusion cells, mean penetration (n = 9) was 14.6 and 42.6 for the methanol and DMSO groups. Urinary metabolites of T-2 were T-2 triol, 3' OH-HT-2, T-2 tetraol, the glucuronide conjugate of HT-2 and several more polar metabolites. The main metabolite of T-2 in the receptor fluid bathing the dermal surfaces of excised skin was HT-2.     

Association of social determinants of health with late diagnosis and survival of patients with pancreatic cancer

BackgroundPancreatic cancer disparities have been described. However, it is unknown if they contribute to a late diagnosis and survival of patients with metastatic disease. Identifying their role is important as it will open the door for interventions. We hypothesize that social determinants of health (SDH) such as income, education, race, and insurance status impact (I) stage of diagnosis of PC (Stage IV vs. other stages), and (II) overall survival (OS) in Stage IV patients.MethodsUsing the National Cancer Database, we evaluated a primary outcome of diagnosis of Stage IV PC and a secondary outcome of OS. Primary predictors included race, income, education, and insurance. Covariates included age, sex and Charlson-Deyo comorbidity score. Univariate, multivariable logistic regression models evaluated risk of a late diagnosis. Univariate, multivariable Cox proportional hazards model examined OS. 95% confidence intervals were used.Results230,877 patients were included, median age of 68 years (SD 12.1). In univariate analysis, a better education, higher income, and insurance decreased the odds of Stage IV PC, while Black race increased it. In multivariable analysis, education [>93% high-school completion (HSC) vs. <82.4%, OR 0.96 (0.93–0.99)] and insurance [private vs. no, OR 0.72 (0.67–0.74)] significantly decreased the risk of a late diagnosis, whereas Black race increased the odds [vs. White, OR 1.09 (1.07–1.12)]. In univariate Cox analysis, having a higher income, insurance and better education improved OS, while Black race worsened it. In multivariable Cox, higher income [>$63,333 (vs. <$40,277), HR 0.87 (0.85–0.89)] and insurance [private vs. no, HR 0.77 (0.74–0.79)] improved OS.ConclusionsSDH impacted the continuum of care for patients with advanced pancreatic cancer, including stage at diagnosis and overall survival.     

Distinct generation, pharmacology, and distribution of sphingosine 1-phosphate and dihydrosphingosine 1-phosphate in human neural progenitor cells

In vivo and in vitro studies suggest a crucial role for Sphingosine 1-phosphate (S1P) and its receptors in the development of the nervous system. Dihydrosphingosine 1-phosphate (dhS1P), a reduced form of S1P, is an agonist at S1P receptors, but the pharmacology and physiology of dhS1P has not been widely studied. The mycotoxin fumonisin B1 (FB(1)) is a potent inhibitor of ceramide synthases and causes selective accumulation of dihydrosphingosine and dhS1P. Recent studies suggest that maternal exposure to FB(1) correlates with the development of neural tube defects (NTDs) in which the neural epithelial progenitor cell layers of the developing brain fail to fuse. We hypothesize that the altered balance of S1P and dhS1P in neural epithelial cells contributes to the developmental effects of FB(1). The goal of this work was first to define the effect of FB(1) exposure on levels of sphingosine and dh-sphingosine and their receptor-active 1-phosphate metabolites in human embryonic stem cell-derived neural epithelial progenitor (hES-NEP) cells; and second, to define the relative activity of dhS1P and S1P in hES-NEP cells. We found that dhS1P is a more potent stimulator of inhibition of cAMP and Smad phosphorylation than is S1P in neural progenitors, and this difference in apparent potency may be due, in part, to more persistent presence of extracellular dhS1P applied to human neural progenitors rather than a higher activity at S1P receptors. This study establishes hES-NEP cells as a useful human in vitro model system to study the mechanism of FB(1) toxicity and the molecular pharmacology of sphingolipid signaling. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.     

3－硝基－1，2，4－三唑类乏氧细胞放射增敏剂的构效关系

为了寻找毒性低、增敏作用强的乏氧细胞放射增敏剂，设计并合成了一系列５－溴－，５－甲基－，和５－未取代的３－硝基－１，２，４－三唑－１－乙酰胺类化合物，用ＨｅＬａＳ３细胞进行了体外试验。结果表明５－溴取代衍生物的增敏作用强于相应的５－甲基－或５－未取代的硝基三唑衍生物，但是它们的毒性亦增大。修饰１位乙酰胺侧链也可以改变化合物的增敏作用和亲脂性。在所测定的化合物中ＴＡ－１０１［２－（３－硝基－１－三唑基）乙酰胺］由于有高的增敏作用和低亲脂性，可能是一个有希望的放射增敏剂。