Trp-Lys-Tyr-Met-Val-D-Met is a chemoattractant for human phagocytic cells

Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm) is a synthetic peptide that stimulates phosphoinositide (PI) hydrolysis in human leukocytes. The peptide binds to a unique cell surface receptor(s). Recently we had demonstrated that human neutrophils, monocytes, and B lymphocytes express this peptide-specific receptor and that stimulation of human leukocytes with the peptide leads to activation of the oxidative respiratory system and the bactericidal activity of neutrophils or monocytes. In this study we showed that the peptide induces chemotaxis of phagocytic leukocytes and studied the signaling pathway leading to chemotaxis in human monocytes. The peptide-induced monocyte chemotaxis is pertussis toxin (PTX)-sensitive. This fact correlates with the peptide's stimulation of PI hydrolysis and intracellular Ca2+ ([Ca2+]i) release, which is also PTX-sensitive. We demonstrate that the peptide-specific receptor is different from receptor(s) for monocyte chemoattractant protein-1 (MCP-1). We also show that intracellular signaling of WKYMVm leading to monocyte chemotaxis is different from that of MCP-1. The peptide-mediated monocyte chemotaxis is insensitive to protein kinase C (PKC) inhibitor (GF109203X) and butan-1-ol, ruling out PKC and phospholipase D participation in this process. On the other hand, a tyrosine kinase inhibitor (genistein) and RhoA inhibitor (C3 transferase) curtailed the peptide-induced chemotaxis in a concentration-dependent manner, implying the involvement of tyrosine kinase and RhoA, respectively. Treatment of human monocytes with the peptide stimulates tyrosine phosphorylation of several cellular proteins, including p125FAK and Pyk2 and translocation of RhoA from the cytosol to the membrane. We conclude that WKYMVm induces chemotaxis of human phagocytic leukocytes via unique receptors and signaling.     

The Effects of Sex,Joint Angle,and the Gastrocnemius Muscle on Passive Ankle Joint Complex Stiffness

OBJECTIVE: To assess the effects of sex, joint angle, and the gastrocnemius muscle on passive ankle joint complex stiffness (JCS). DESIGN AND SETTING: A repeated-measures design was employed using sex as a between-subjects factor and joint angle and inclusion of the gastrocnemius muscle as within-subject factors. All testing was conducted in a neuromuscular research laboratory. SUBJECTS: Twelve female and 12 male healthy, physically active subjects between the ages of 18 and 30 years volunteered for participation in this study. The dominant leg was used for testing. No subjects had a history of lower extremity musculoskeletal injury or circulatory or neurologic disorders. MEASUREMENTS: We determined passive ankle JCS by measuring resistance to passive dorsiflexion (5 degrees.s(-1)) from 23 degrees plantar flexion (PF) to 13 degrees dorsiflexion (DF). Angular position and torque data were collected from a dynamometer under 2 conditions designed to include or reduce the contribution of the gastrocnemius muscle. Separate fourth-order polynomial equations relating angular position and torque were constructed for each trial. Stiffness values (Nm.degree(-1)) were calculated at 10 degrees PF, neutral (NE), and 10 degrees DF using the slope of the line at each respective position. RESULTS: Significant condition-by-position and sex-by-position interactions and significant main effects for sex, position, and condition were revealed by a 3-way (sex-by-position, condition-by-position) analysis of variance. Post hoc analyses of the condition-by-position interaction revealed significantly higher stiffness values under the knee-straight condition compared with the knee-bent condition at both ankle NE and 10 degrees DF. Within each condition, stiffness values at each position were significantly higher as the ankle moved into DF. Post hoc analysis of the sex-by-position interaction revealed significantly higher stiffness values at 10 degrees DF in the male subjects. Post hoc analysis of the position main effect revealed that as the ankle moved into dorsiflexion, the stiffness at each position became significantly higher than at the previous position. CONCLUSIONS: The gastrocnemius contributes significantly to passive ankle JCS, thereby providing a scientific basis for clinicians incorporating stretching regimens into rehabilitation programs. Further research is warranted considering the cause and application of the sex-by-position interaction.     

Modulation of excitatory amino acid responses in rat dorsal horn neurons by tachykinins.

1. In freshly isolated spinal dorsal horn (DH) neurons (laminae I-III) of the young rat, the effects of tachykinins (substance P, neurokinin A) on inward current induced by excitatory amino acids were studied under whole-cell voltage-clamp conditions. 2. When the cells were clamped to a holding potential of -60 mV, a simultaneous application of N-methyl-D-aspartate (NMDA) (10(-4) M) and substance P (SP) (2 x 10(-9)-10(-7) M) for 10 s reversibly enhanced (by 129.6 +/- 8.2%, mean +/- SE) the peak amplitude of the initial transient component of the NMDA-induced current in approximately 60% of the examined cells and reduced it (to 83.3 +/- 2.7%) in 27% of the cells. In addition, SP produced an increase (by 133.6 +/- 11.7%) or a small decrease (to 85.9 +/- 1.4%) in the steady-state component of the NMDA response. In difference to SP, a simultaneous application of NMDA (10(-4) M) and neurokinin A (NKA) (10(-10)-10(-7) M) reversibly suppressed (to 86.8 +/- 2.1%) the peak amplitude of the NMDA-induced current in 75% of the examined cells. 3. The NMDA-induced currents were modulated by tachykinins not only during the coadministration but up to 20 min after the removal of the peptide. SP potentiated the initial peak NMDA current by 147.9 +/- 8.1% in 78% of examined cells and decreased it (76.3 +/- 5.7%) in 11% of cells. The potentiating effect was concentration-dependent (range: 10(-11)-10(-8) M) and reversible, but it was reduced with repeated applications. In addition, SP increased (by 125.4 +/- 3.6%) or reduced (to 86.0 +/- 1.8%) the steady-state component of the NMDA response. 4. When the single DH neurons were exposed to SP or NKA for 30 s-7 min before the testing of the NMDA responses, tachykinins had two distinct effects on the peak amplitude of the transient component of the NMDA-induced current, consisting of an initial depression (SP: to 64.8 +/- 2.1%; NKA: to 76.3 +/- 4.4%) followed by a potentiation (SP: by 146.6 +/- 6.8%; NKA: by 178.4 +/- 35.2%). The enhancing effect in some cells lasted less than or equal to 1 h. 5. A claimed novel nonselective tachykinin antagonist, spantide II (10(-8) M) coadministered with NMDA (10(-4) M), slightly depressed the peak component of NMDA-induced current. In addition, it effectively blocked the SP-induced potentiation of the responses of DH neurons to NMDA.(ABSTRACT TRUNCATED AT 400 WORDS)     

Atypical clinical manifestations of amebic colitis.

Amebic colitis is a disease revealing diverse clinical manifestations and endoscopic gross features and often confused with other types of colitis. In case of misdiagnosis as an idiopathic inflammatory bowel disease or delayed recognition of intestinal amebiasis, an undesirable outcome may occur resulting from erroneous administration of steroids or delayed antiamebic treatment. To demonstrate the pitfalls in the diagnosis and treatment of intestinal amebiasis, 3 cases of amebic colitis with atypical clinical manifestations are presented in this paper. In conclusion, despite the low sensitivities of routine stool examination for parasite and histopathologic confirmation in biopsy specimen, every effort must be made to find amebic trophozoites either in fresh stool or biopsy specimens for prompt and correct diagnosis of amebic colitis when we manage patients with chronic intestinal ulcerations, even though their clinical course and endoscopic findings are not typical of amebiasis. Moreover, following initial successful anti-amebic therapy, more careful clinical, endoscopical, and parasitological follow-up should be done for the early detection of recurrence.     

Cognitive Deficits in Type-1 Diabetes: Aspects of Glucose,Cerebrovascular and Amyloid Involvement

Pharmaceutical Research - The evidence shows that individuals with type-1 diabetes mellitus (T1DM) are at greater risk of accelerated cognitive impairment and dementia. Although, to date the...     

Outcomes of lung cancer surgery in patients with coronary artery disease: a decade of experience at a single institution

Purpose

The aim of this study is to investigate the surgical outcomes of surgery for non-small cell lung cancer (NSCLC) in patients with coronary artery disease (CAD).

Methods

Among 805 patients who underwent surgery for NSCLC at our hospital within a recent 10-year period, 43 (5.3 %) had a history of CAD. We analyzed the surgical outcomes and risk factors for postoperative complications in these 43 patients.

Results

The postoperative mortality and morbidity rates were 2 and 42 %, respectively. The morbidity rate was significantly higher in the patients with CAD than in those without CAD (P < 0.01). Postoperative cerebrovascular or cardiovascular events occurred in four patients (9 %). Having two of the following was significantly associated with the development of postoperative complications: decreased cardiac function, respiratory dysfunction, or deteriorated renal function (p = 0.04). The 5-year overall and disease-free survival rates of the patients with CAD were 75.6 and 64.5 %, respectively; comparable with those of the patients without CAD; at 77.9 % and 72.5 %, respectively (p = 0.46 and 0.69).

Conclusions

Patients with NSCLC and a history of CAD are at higher risk of complications after pulmonary resection. Combined decreased organ function is a risk factor for postoperative complications. CAD did not influence the long-term outcomes of patients after pulmonary resection for NSCLC.

     

Effects of cell penetrating Notch inhibitory peptide conjugated to elastin-like polypeptide on glioblastoma cells

Notch pathway was found to be activated in most glioblastomas (GBMs), underlining the importance of Notch in formation and recurrence of GBM. In this study, a Notch inhibitory peptide, dominant negative MAML (dnMAML), was conjugated to elastin-like polypeptide (ELP) for tumor targeted delivery. ELP is a thermally responsive polypeptide that can be actively and passively targeted to the tumor site by localized application of hyperthermia. This complex was further modified with the addition of a cell penetrating peptide, SynB1, for improved cellular uptake and blood–brain barrier penetration. The SynB1–ELP1–dnMAML was examined for its cellular uptake, cytotoxicity, apoptosis, cell cycle inhibition and the inhibition of target genes’ expression. SynB1–ELP1–dnMAML inhibited the growth of D54 and U251 cells by inducing apoptosis and cell cycle arrest, especially in the presence of hyperthermia. Hyperthermia increased overall uptake of the polypeptide by the cells and enhanced the resulting pharmacological effects of dnMAML, showing the inhibition of targets of Notch pathway such as Hes-1 and Hey-L. These results confirm that dnMAML is an effective Notch inhibitor and combination with ELP may allow thermal targeting of the SynB1–ELP1–dnMAML complex in cancer cells while avoiding the dangers of systemic Notch inhibition.