Higher rate of progesterone receptor positivity in skeletal metastases of breast cancer with a pathological fracture vs those without fracture.

Identifying risk factors for fracture occurrence in breast cancer (BC) skeletal metastases (SM) may guide the management of such bone deposits. There is sparse evidence regarding receptor status in SM and their relationship to fracture occurrence. Our study aimed to determine the relationship between estrogen (ER), progesterone (PR) and HER2 receptor status and Ki-67 index and fracture occurrence in SM of BC. Exactly 152 samples of SM of BC obtained from individual patients were evaluated. The status of the aforementioned receptors and Ki67 index were determined in SMs samples. Their expression was compared between SM that did and did not develop a fracture. Ninety-one cases sustained a pathological fracture at the SM site, and 61 did not. Patients who sustained a pathological fracture had a higher rate of PR positivity at their SMs as compared to those with no fracture. There was no significant difference between the two groups concerning ER, HER2+ or Ki67 status. SMs secondary to BC with a fracture are more likely to be PR positive than those with no fracture. Determining the receptor status in SMs may identify high-risk groups for fracture occurrence, and determining the PR status may also guide surgical and hormonal therapy.

Mechanical and Contractile Properties of Knee Joint Muscles Measured by the Method of Tensiomyography in Differently Trained Men and Women.

ABSTRACT: Toskic, LD, Dopsaj, MJ, Markovic, MR, Toskic, DR, Ignjatovic, AM. Mechanical and contractile properties of knee joint muscles measured by the method of tensiomyography in differently trained men and women. J Strength Cond Res 36(6): 1532-1539, 2022-The aim of this study was to investigate the differences in mechanical and contractile properties of knee joint flexor and extensor muscles between differently trained men and women, using tensiomyography (TMG). The sample consisted of 159 subjects (84 men and 75 women), who were assigned to one of 5 groups according to the following levels and types of their physical activity: physically inactive, physically active nonathletes, strength and power athletes, endurance athletes, and team sports athletes. Measurements were performed on the following knee flexor and extensor muscles of the dominant leg: rectus femoris, vastus medialis, vastus lateralis, biceps femoris, and semitendinosus. The results showed significant differences in contraction time-Tc (F = 1.911, p = 0.010) and delay time-Td (F = 1.989, p = 0.007) parameters between differently trained men and women, whereas in other TMG parameters, there were no differences between groups. It is indicated that physical activities characteristic of strength and power sports (combat sports and sprint disciplines) could lead to an increased speed of twitch force generation and fast twitch muscle fibers, and that almost any regular, systematic, and planned physical activity leads to increased muscle responsiveness. Obtained results also indicated that TMG parameters do not have enough specific discriminatory power for detecting differences between differently trained young adults.

East-West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort.

OBJECTIVE: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East-West gradient in the incidence of IBD in Europe exists. DESIGN: A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. RESULTS: 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100,000 in 2010 for CD were 6.5 (range 0-10.7) in Western European centres and 3.1 (range 0.4-11.5) in Eastern European centres, for UC 10.8 (range 2.9-31.5) and 4.1 (range 2.4-10.3), respectively, and for IBDU 1.9 (range 0-39.4) and 0 (range 0-1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. CONCLUSIONS: An East-West gradient in IBD incidence exists in Europe. Among this inception cohort--including indolent and aggressive cases--international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

Fetal lung volume and quantification of liver herniation by magnetic resonance imaging in isolated congenital diaphragmatic hernia.

OBJECTIVE: To determine associations between fetal lung and liver herniation volumes measured by magnetic resonance imaging (MRI) and mortality/need for extracorporeal membrane oxygenation (ECMO) in cases of isolated congenital diaphragmatic hernia (CDH). A secondary objective was to compare prenatal MRI parameters with two-dimensional ultrasound lung measurements. METHODS: A retrospective review of medical records of all fetuses with isolated CDH evaluated between January 2004 and July 2012 was performed. The following MRI parameters were measured at 20-32 weeks: observed/expected total fetal lung volume (o/e-TLV), predicted pulmonary volume (PPV), percentage of liver herniated into the fetal thorax (%LH) and the liver/thoracic volume ratio (LiTR). These were compared with the ultrasound-determined lung-to-head ratio (LHR) and the observed/expected LHR (o/e-LHR) in the same cohort. The predictive value of MRI and ultrasound parameters for mortality and the need for ECMO was evaluated by univariate, multivariate and factor analysis and by receiver-operating characteristics curves. RESULTS: Eighty fetuses with isolated CDH were evaluated. Overall mortality was 18/80 (22.5%). Two newborns died a few hours after birth. ECMO was performed in 29/78 (37.2%) newborns, with a survival rate of 48.3% (14/29). The side of the diaphragmatic defect was not associated with mortality (P = 0.99) or the need for ECMO (P = 0.48). Good correlation was observed among o/e-TLV, PPV, LHR and o/e-LHR as well as between %LH and LiTR (r = 0.89; P < 0.01); however, fetal lung measurements and measures of liver herniation were not correlated (all P > 0.05). All parameters were statistically associated with mortality or the need for ECMO. The best combination of measurements to predict mortality was o/e-TLV and %LH, with 83% accuracy. CONCLUSION: Mortality and the need for ECMO in neonates with isolated CDH can be best predicted using a combination of MRI o/e-TLV and %LH.

Standardizing the skin tape stripping method for sensitization and using it to create a mouse model of peanut allergy.

BACKGROUND: Animal models for food allergies serve as crucial tools in understanding allergy mechanisms and assessing the efficacy of potential desensitization methods. The effectiveness of inducing allergies in mice through intragastric lavage sensitization varies. The intraperitoneal method can trigger systemic anaphylaxis, however it lacks anatomical relevance. Hence, a uniform and reliable allergy induction method in mice is required. Tape -stripping can mimic atopic dermatitis (AD), a precursor to lifelong peanut allergies in humans. Furthermore, skin damage triggers the upregulation of skin alarmins and the expansion of small-intestinal mast cells, both implicated in allergy development. METHODS: We standardized a skin-based sensitization method in a mouse model of peanut allergy using skin tape-stripping followed by allergen application. We compared this method with intragastric sensitization. RESULTS: Skin-based sensitization led to increased mast cells, goblet cells, and eosinophils in the small intestine, elevated systemic IgE levels, murine mast cell protease-1 (mMCP-1), histamine, and eosinophilic activity in peripheral blood. Moreover, it resulted in a significant hypothermic response, with nearly 30% mortality following an oral challenge one-month post-sensitization. CONCLUSION: Our research offers a standardized and readily reproducible method for inducing peanut allergy in mice, which could also be adapted for other food allergens.

Development of a mini pig model of peanut allergy.

Introduction: The prevalence of peanut allergies is increasing, emphasizing the need for an animal model to enhance our understanding of peanut allergy pathogenesis and to advance diagnostic tools and therapeutic interventions. While mice are frequently used as model organisms, their allergic responses do not fully mirror those observed in humans, warranting the exploration of a higher animal model. The porcine gastrointestinal system closely resembles that of humans, and exhibits allergy symptoms akin to human responses, making pigs a promising model for peanut allergy research. Methods: In this study we compared two allergen sensitization protocols involving either topical allergen application after repeated tape stripping (TS) or intraperitoneal (IP) injections to induce peanut-specific allergy and anaphylaxis reactions in mini pigs. Mini pigs sensitized with a combination of peanut protein extract (PE) and cholera toxin (CT) through either the IP or the TS route. Results: Sensitized pigs via both methods developed systemic PE-specific IgG and IgE responses. Following peanut challenge via the IP route, both TS- and IP-sensitized pigs displayed allergy symptoms, including lethargy, skin rashes, vomiting, and a drop in body temperature. However, respiratory distress was observed exclusively in pigs sensitized through the TS route and not in those sensitized through the IP route. However, it is noteworthy that both groups of sensitized pigs maintained peanut hypersensitivity for up to two months post-sensitization, albeit with a reduction in the severity of allergy symptoms. Importantly, both groups exhibited sustained levels of PE-specific IgG, IgE, and elevated concentrations of mast cell protease in their blood following the IP challenges. Discussion: Overall, this study reports TS and IP as two different modes of sensitization leading to onset of peanut specific allergic reactions in mini pigs, but only the TS-sensitization led to systemic anaphylaxis (simultaneous presence of symptoms: breathing difficulty, intense skin rash, and impaired mobility). A distinctive feature of these sensitization protocols is the 100% success rate (N = 4 pigs per group) in sensitizing the subjects.

Delivery of gold nanoparticle-conjugated M2e influenza vaccine in mice using coated microneedles.

As a prospective influenza vaccination platform, a microneedle patch offers advantages such as self-administration and reduction of needle-phobia-associated vaccination avoidance. In an effort to design a broadly protective influenza vaccine we have previously developed a vaccine formulation containing the highly conserved ectodomain sequence of the M2 influenza protein (M2e) attached to the surface of gold nanoparticles (AuNPs) with CpG as a soluble adjuvant (AuNP-M2e + sCpG). Our previous studies have used the intranasal route for vaccination and demonstrated broad protection from this vaccine. Here we asked the question whether the same formulation can be effective when administered to mice using microneedles. We demonstrate that the microneedles can be coated with AuNP-M2e + sCpG formulation, and the AuNPs from the coating can be readily resuspended without aggregation. The AuNPs were delivered with high efficiency into murine skin, and the AuNPs cleared the skin within 12 h of microneedle treatment. After vaccination, strong M2e-specific humoral and cellular responses were stimulated, and the vaccinated mice were 100% protected following a lethal challenge with influenza A/PR/8/34 (H1N1).

Treating allergies via skin - Recent advances in cutaneous allergen immunotherapy.

Subcutaneous allergen immunotherapy has been practiced clinically for decades to treat airborne allergies. Recently, the cutaneous route, which exploits the immunocompetence of the skin has received attention, which is evident from attempts to use it to treat peanut allergy. Delivery of allergens into the skin is inherently impeded by the barrier imposed by stratum corneum, the top layer of the skin. While the stratum corneum barrier must be overcome for efficient allergen delivery, excessive disruption of this layer can predispose to development of allergic inflammation. Thus, the most desirable allergen delivery approach must provide a balance between the level of skin disruption and the amount of allergen delivered. Such an approach should aim to achieve high allergen delivery efficiency across various skin types independent of age and ethnicity, and optimize variables such as safety profile, allergen dosage, treatment frequency, application time and patient compliance. The ability to precisely quantify the amount of allergen being delivered into the skin is crucial since it can allow for allergen dose optimization and can promote consistency and reproducibility in treatment response. In this work we review prominent cutaneous delivery approaches, and offer a perspective on further improvisation in cutaneous allergen-specific immunotherapy.

Early and Late Mortality Predictors in Patients with Acute Aortic Dissection Type B.

Background/Aim: Despite technological advances in diagnosis and treatment, in-hospital mortality with acute aortic dissection type B is still about 11%. The purpose of this study was to assess the risk factors for early and long-term adverse outcomes in patients with acute aortic dissection type B treated medically or with conventional open surgery. Methods: The present study included 104 consecutive patients with acute aortic dissection type B treated in our Center from January 1st, 1998 to January 1st, 2007. Patient demographic and clinical characteristics as well as in-hospital complications were reviewed. Univariate and multivariate testing was performed to identify the predictors of in-hospital (30-day) and late (within 9 years) mortality. Results: 92 (88.5%) patients were treated medically, while 12 (11.5%) patients with complicated acute aortic dissection type B were treated by open surgical repair. In-hospital complications occurred in 35.7% patients, the most often being acute renal failure (28%), hypotension/shock (24%), mesenteric ischemia (12%), and limb ischemia (8%). The in-hospital mortality rate was 15.7% and the 9-year mortality rate was 51.9%. Independent predictors of early mortality in patients with acute aortic dissection type B were uncontrolled hypertension (HR-20.69) and a dissecting aorta diameter >4.75 cm (HR-6.30). Independent predictors of late mortality were relapsing pain (HR-7.93), uncontrolled hypertension (HR-7.25), and a pathologic difference in arterial blood pressure (>20 mmHg) (HR-5.33). Conclusion: Knowledge of key risk factors may help with a better choice of treatment and mortality reduction in acute aortic dissection type B patients.

Treatment Steps, Surgery, and Hospitalization Rates During the First Year of Follow-up in Patients with Inflammatory Bowel Diseases from the 2011 ECCO-Epicom Inception Cohort.

BACKGROUND AND AIMS: The ECCO-EpiCom study investigates the differences in the incidence and therapeutic management of inflammatory bowel diseases [IBD] between Eastern and Western Europe. The aim of this study was to analyse the differences in the disease phenotype, medical therapy, surgery, and hospitalization rates in the ECCO-EpiCom 2011 inception cohort during the first year after diagnosis. METHODS: Nine Western, five Eastern European centres and one Australian centre with 258 Crohn's disease [CD], 380 ulcerative colitis [UC] and 71 IBD unclassified [IBDU] patients [female/male: 326/383; mean age at diagnosis: 40.9 years, SD: 17.3 years] participated. Patients' data were registered and entered in the web-based ECCO-EpiCom database [www.epicom-ecco.eu]. RESULTS: In CD, 36 [19%] Western Europe/Australian and 6 [9%] Eastern European patients received biological therapy [p = 0.04], but the immunosuppressive [IS] use was equal and high in these regions [Eastern Europe vs Western Europe/Australia: 53% vs 45%; p = 0.27]. Surgery was performed in 17 [24%] CD patients in Eastern Europe and 13 [7%] in Western Europe/Australia [p < 0.001, pLogRank = 0.001]. Of CD patients from Eastern Europe, 24 [34%] were hospitalized, and 39 [21%] from Western Europe/Australia, [p = 0.02, pLogRank = 0.01]. In UC, exposure to biologicals and colectomy rates were low and hospitalization rates did not differ between these regions during the 1-year follow-up period [16% vs 16%; p = 0.93]. CONCLUSIONS: During the first year after diagnosis, surgery and hospitalization rates were significantly higher in CD patients in Eastern Europe compared with Western Europe/Australia, whereas significantly more CD patients were treated with biologicals in the Western Europe/Australian centres.

Lipid bilayer in genetic hypertension.

Membrane microviscosity, phospholipid composition, and turnover were measured in cultured vascular smooth muscle cells isolated from mesenteric arteries of stroke-prone spontaneously hypertensive and age-matched, normotensive Wistar-Kyoto rats. Membrane microviscosity, measured with fluorescence polarization, revealed greater microviscosity (lower fluidity) of the membranes isolated from smooth muscle cells from hypertensive as compared with those isolated from normotensive rats (p less than 0.01). Preincubation of membranes from hypertensive rats with 5 mM calcium reduced membrane microviscosity in "core" and in "surface" regions of the bilayer toward values observed in Wistar-Kyoto rats. Phospholipid composition did not differ between intact aortas and cultured mesenteric cells or between those tissues obtained from normotensive and from hypertensive rats. The total lipid-associated radioactivity was significantly lower in cells from stroke-prone spontaneously hypertensive rats than in those from Wistar-Kyoto controls (p less than 0.01). Phosphatidylcholine incorporated 70% and phosphatidylinositol 16% of total lipid-associated radioactivity, with no difference between cells from hypertensive and normotensive animals. Turnover of phosphatidylethanolamine was greater in cells from Wistar-Kyoto rats (p = 0.02), whereas turnover of phosphatidylserine was greater in cells from stroke-prone spontaneously hypertensive rats (p = 0.04). The greater microviscosity of the lipid bilayer in hypertension is a generalized defect of the matrix in which the transport proteins function. We hypothesize that this defect is responsible for the multiple abnormalities of membrane transport systems that have been described in genetic hypertension.

Determination of the antenna heterogeneity of Photosystem II by direct simultaneous fitting of several fluorescence rise curves measured with DCMU at different light intensities.

Several methods for determination of the antenna heterogeneity of Photosystem II from fluorescence rise curves measured with DCMU have been developed so far. Using these methods, two, three or four types of Photosystem II with respect to the antenna heterogeneity were determined. However, the accuracy of some of these methods is under debate. Here, we present a new method for the determination of the antenna heterogeneity of Photosystem II. The method is based on direct simultaneous fitting of several fluorescence rise curves measured with DCMU at different intensities of light excitation. As several curves measured under different light conditions are fitted simultaneously by the same model, reliability and accuracy in determination of model parameters increase. Our method was applied to two plant materials with different structure of the thylakoid membrane: wheat leaves and cells of green alga Chlamydomonas reinhardtii.

Thermoluminescence and fluorescence study of changes in Photosystem II photochemistry in desiccating barley leaves.

An effect of desiccation (a decrease of relative water content from 97% to 10% within 35 h) on Photosystem II was studied in barley leaf segments (Hordeum vulgare L. cv. Akcent) using chlorophyll a fluorescence and thermoluminescence (TL). The O-J-I-P fluorescence induction curve revealed a decrease of F(P) and a slight shift of the J step to a shorter time with no change in its height. The analysis of the fluorescence decline after a saturating light flash revealed an increased portion of slow exponential components with increasing desiccation. The TL bands obtained after excitation by continuous light were situated at about -27 degrees C (Z(v) band - recombination of P680(+)Q(A) (-)), -14 degrees C (A band - S(3)Q(A) (-)), +12 degrees C (B band - S(2/3)Q(B) (-)) and +45 degrees C (C band - TyrD(+)Q(A) (-)). The bands related to the S-states of oxygen evolving complex (A and B) were reduced by desiccation and shifted to higher and lower temperatures, respectively. In accordance with this, the band observed at about +27 degrees C (S(2)Q(B) (-)) after excitation by 1 flash fired at -10 degrees C and band at about +20 degrees C (S(2/3)Q(B) (-)) after 2 flashes decreased with increasing water deficit and shifted to lower temperatures. A new band around 5 degrees C appeared in both regimes of TL excitation for a relative water content of under 42% and was attributed to the Q band (S(2)Q(A) (-)). It is suggested that under desiccation, an inhibition of the formation of S(2)- and S(3)-states in OEC occurred simultaneously with a lowering of electron transport on the acceptor side of PS II. The temperature down-shift of the TL bands obtained after the flash excitation was induced at the initial phases of water stress, indicating a decrease of the activation energy for the S(2/3)Q(B) (-)recombination.

Comparison of homoeologous group-6 short arm physical maps of wheat and barley reveals a similar distribution of recombinogenic and gene-rich regions.

Eighty two new loci, mapped with 51 DNA clones, were added to the earlier deletion maps of the homoeologous group-6 short arms of hexaploid wheat ( Triticum aestivum L. em Thell., 2n = 6 x = 42, AABBDD). There are now 41, 56 and 52 loci mapped on deletion maps of 6AS, 6BS and 6DS, respectively. The linear order of orthologous loci in all three arms appears to be identical. The majority of the loci are located in the distal one-half of the three arms. There seems to be an increased marker/gene density from the centromeric to the telomeric regions in each arm, and the marker density in comparable physical regions is similar on all three maps. Recombination is not uniformly distributed along the chromosome arms; 60% of recombination occurs in the distal one-third of each arm. Recombination increases from the proximal region to the distal end in a nonlinear pattern. The distribution of loci and recombination along each of the three chromosome arms is highly correlated. Comparison of the 6BS deletion map from this study and a 6HS physical map of barley ( Hordeum vulgare L., 2n = 2 x = 14, HH) reveals a remarkably similar distribution of recombinogenic and gene-rich regions between the two chromosome arms, suggesting that the distribution patterns of genes may be conserved in the homoeologous group-6 chromosome short arms of wheat and barley. A consensus map of wheat group-6 short arms containing 46 orthologous loci was constructed. Comparison of the consensus map with published linkage maps of Triticeae group-6 chromosome short arms indicates that the linear order of the loci on the maps has been largely conserved. Evidence from this study does not support the existence of a 2BS-6BS reciprocal terminal translocation.

Analgesia elicited by OFQ/nociceptin and its fragments from the amygdala in rats.

The heptadecapeptide, orphanin FQ/nociceptin (OFQ/N), binds with high affinity to the ORL-1/KOR-3 opioid receptor clone, yet binds poorly with traditional opioid receptors. OFQ/N has a complex functional profile with relation to nociceptive processing, displaying pro-nociceptive properties in some studies, acting as an inhibitor of stress-induced analgesia in others, yet producing both spinal and supraspinal antinociceptive actions in other studies. Among the intracerebral sites at which OFQ/N might produce one or more of these actions is the amygdala which has been intimately implicated in both antinociceptive and stress-related responses. Therefore, the present study assessed whether microinjections into the amygdala of equimolar doses of OFQ/N(1-17) or its shorter-chained active fragments, OFQ/N(1-11) or OFQ/N(1-7), would produce analgesia as measured by either reactivity to high-intensity radiant heat or reactivity to electric shock, and produce hyperalgesia as measured by reactivity to lower-intensity radiant heat. OFQ/N(1-17) in the amygdala produced a dose-dependent and time-dependent increase in high-intensity tail-flick latencies with maximal effects observed at a dose range of 0.75-3 nmol, and lesser effects at lower (0.015-0.15 nmol) and higher (5.5-30 nmol) doses. Both OFQ/N(1-11) and OFQ/N(1-7) in the amygdala displayed lower magnitudes of analgesia than OFQ/N(1-17) on this measure, with OFQ/N(1-11) displaying maximal effects at higher (15-30 nmol) doses and OFQ/N(1-7) displaying maximal effects at lower (0.15-1.5 nmol) doses. In contrast to traditional mu and kappa opioids and beta-endorphin, none of the OFQ/N fragments in the amygdala exhibited any analgesic responses on the jump test. Finally, using a low-intensity radiant heat assay capable of detecting hyperalgesic responses, each of the OFQ/N fragments in the amygdala increased tail-flick latencies on this measure. Therefore, OFQ/N fragments appear to exert only analgesic responses in the amygdala with quantitative and qualitative differences relative to traditional opioid agonists.

Mathematical modelling of 3-(3',4'-dichlorophenyl)-1,1-dimenthylurea action in plant leaves

A mathematical model of the action of a photosystem II herbicide 3-(3',4'-dichlorophenyl)-1, 1-dimenthylurea, DCMU, in plant leaves upon an external application is presented. The diffusion of DCMU in a plant tissue is described with the help of Fick's laws and the following reaction of the herbicide with the QB-binding site of photosystem II by the mass action theory. The model is used for a description of the effect of the herbicide on chlorophyll fluorescence induction (the O-J-I-P curve) measured with spring barley primary leaves submerged in the herbicide solution. The increase of the J step during the herbicide action is ascribed to an increase of the number of photosystem II centres with bound herbicide molecules and malfunctioning in the electron transport to the plastoquinone pool. The experimental data were fitted with the help of the mathematical model. Values of the diffusion coefficient and the second order rate constant of the reaction of the herbicide with photosystem II, obtained by the fitting procedure, are discussed.Copyright 1998 Academic Press Limited

Enhancement of adenosine A1 receptor functions by benzoylthiophenes in guinea pig tissues in vitro.

Previous reports on a series of benzoylthiophenes, including PD 81,723 [2-amino-4,5-dimethyl-3-(3-trifluoromethyl-benzoyl) thiophene], have shown specific enhancement of agonist binding at the adenosine A1 receptor. We have studied the effects of two substituted benzoylthiophenes, PD 78,416 (thieno[2,3-c]pyridine-6(5H)-carboxylic acid, 2-amino-3-benzoyl-4,7-dihydro-ethyl ester) and RS-74513-000 [2-amino-4-ethyl-5-methyl-3-(3-trifluoro-methyl-benzoyl) thiophene] on response elicited by adenosine A1 receptors in isolated guinea pig left atrium and ileum. In the electrically paced left atrium, PD 78,416 antagonized negative inotropic effect elicited by the agonist CPA [N6-cyclopentyladenosine] with a pKB value of 6.2 +/- 0.2 (n = 4). At a low concentration which had no antagonistic effect (0.1 microM), PD 78,416 enhanced the effect of CPA. The concentration-response curve to CPA was shifted leftward by 5.1 fold (95% confidence limits 2.4-11.2). In field stimulated isolated ileum, PD 78,416 (0.1, 0.3, 1 microM) did not enhance or antagonize effects of CPA. At concentrations above 1 microM, PD 78,416 decreased electrically induced contraction. This effect was not sensitive to adenosine deaminase and was not antagonized by the A1 antagonist CPX [8-cyclopentyl-1,3-dipropyl-xanthine] (1 microM). Unlike PD 78,416, RS-74513-000 (0.01, 0.1, 1, 3, 10 microM) did not antagonize or enhance effects of CPA in the left atrium. However, effects of CPA in ileum were enhanced by RS-74513-000 (1 and 3 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of macrophage and microglial responses to axonal injury in the peripheral and central nervous systems.

OBJECTIVE: After axonal injury, macrophages rapidly infiltrate and become activated in the mammalian peripheral nervous system (PNS) but not the central nervous system (CNS). We used the dorsal root pathway to study factors that modulate the response of macrophages to degenerating axons in both the PNS and the CNS. METHODS: Lewis rats underwent transection of dorsal roots (Group 1), stab within the spinal cord (Group II), crush at the dorsal root entry zone (Group III), transection of dorsal roots combined with a CNS lesion (Group IV), or systemic administration of a known activator of macrophages, lipopolysaccharide, alone (Group V) or combined with transection of dorsal roots (Group VI). ED-1 antibody stained for macrophages and activated microglia at 7, 14, and 42 days postinjury. RESULTS: At early time points, Group I demonstrated ED-1 cells in the PNS but not the CNS portion of the degenerating dorsal roots. Group II revealed ED-1 cells near the stab lesion. Group III demonstrated ED-1 cells adjacent to the dorsal root entry zone crush site. Group IV revealed ED-1 cells along both the PNS and the CNS portions of the degenerating dorsal roots when the CNS lesion was placed near the transected roots. Group V demonstrated few ED-1 cells in the PNS and the CNS, whereas Group VI revealed a marked ED-1 cellular response along both the PNS and the CNS portions of the transected dorsal roots. CONCLUSION: Local CNS trauma and systemic administration of lipopolysaccharide can "prime" macrophages/microglia, resulting in an enhanced response to degenerating axons in the CNS. Such priming might prove useful in promoting axonal regeneration.

Ultrasound accelerates functional recovery after peripheral nerve damage.

OBJECTIVE: Axonal injury in the peripheral nervous system is common, and often it is associated with severe long-term personal and societal costs. The objective of this study is to use an animal model to demonstrate that transcutaneous ultrasound can accelerate recovery from an axonotmetic injury. METHODS: The sciatic nerve of adult male Lewis rats was crushed in the right midthigh to cause complete distal degeneration of axons yet maintain continuity of the nerve. Beginning 3 days after surgery, various transcutaneous ultrasound treatments or sham treatments were applied 3 days per week for 30 days to the crush site of rats that were randomly assigned to two groups. In the preliminary experiments, there were three animals in each ultrasound group and two control animals. In the final experiment, there were 22 animals in the ultrasound group and 20 animals in the control group. Recovery was assessed by use of a toe spread assay to quantify a return to normal foot function in the injured leg. Equipment included a hand-held transducer that emitted continuous-wave ultrasound. The most successful ultrasound protocol had a spatial peak, time-averaged intensity of 0.25 W/cm2 operated at 2.25 MHz for 1 minute per application. RESULTS: Rats subjected to the most successful ultrasound protocol showed a statistically significant acceleration of foot function recovery starting 14 days after injury versus 18 days for the control group. Full recovery by the ultrasound group occurred before full recovery by the control group. CONCLUSION: Transcutaneous ultrasound applied to an animal model of axonotmetic injury accelerated recovery. Future studies should focus on identification of the mechanism(s) by which ultrasound creates this effect, as a prelude to optimization of the protocol, demonstration of its safety, and its eventual application to humans.

Acceleration of recovery after injury to the peripheral nervous system using ultrasound and other therapeutic modalities.

Taken together, these studies show the promise of various therapeutic modalities for the noninvasive treatment of peripheral nerve injury. Further progress on these promising methods requires determining the biologic mechanisms responsible for the ability of these modalities to enhance peripheral nerve recovery. Necessary investigations include validation or refutation of the hypothesis that these therapies act on various aspects of the natural healing process. Examples include cellular and molecular processes involved in promoting Wallerian degeneration and the rate and specificity of axonal regeneration and remyelination and muscle reinnervation, processes that are distributed between the regenerating nerve itself, the pathway of the regenerating axon, and the target of the regenerating nerve. An increased understanding of the biologic mechanisms underlying the enhancement of peripheral nerve recovery after injury would lend greater insight into the cellular and molecular mechanisms involved in successful nerve regeneration and muscle reinnervation. This increased understanding may also result in clinically beneficial treatments for peripheral nerve disorders.