Impact of diabetes and hypertension on cardiovascular outcomes in patients with coronary artery disease receiving percutaneous coronary intervention.

BACKGROUND: Percutaneous coronary intervention (PCI) is a necessary procedure commonly performed for patients with coronary artery disease (CAD). However, the impact of diabetes and hypertension on long-term outcomes of patients after receiving PCI has not yet been determined. METHODS: The data of 1234 patients who received PCI were collected prospectively, and patients were divided into four groups, including patients with and without DM and those with either DM or hypertension alone. Baseline characteristics, risk factors, medications and angiographic findings were compared and determinants of cardiovascular outcomes were analyzed in patients who received PCI. RESULTS: Patients with DM alone had the highest all-cause mortality (P < 0.001), cardiovascular mortality and myocardial infarctions (MI) (both P < 0.01) compared to the other groups. However, no differences were found between groups in repeat PCI (P = 0.32). Cox proportional hazard model revealed that age, chronic kidney disease (CKD), previous MI and stroke history were risk factors for all-cause mortality (OR: 1.05,1.89, 2.87, and 4.12, respectively), and use of beta-blockers (BB) and statins reduced all-cause mortality (OR: 0.47 and 0.35, respectively). Previous MI and stroke history, P2Y12 inhibitor use, and syntax scores all predicted CV mortality (OR: 4.02, 1.89, 2.87, and 1.04, respectively). Use of angiotensin converting enzyme inhibitors (ACEI), beta-blockers (BB), and statins appeared to reduce risk of CV death (OR: 0.37, 0.33, and 0.32, respectively). Previous MI and syntax scores predicted MI (OR: 3.17 and 1.03, respectively), and statin use reduced risk of MI (OR: 0.43). Smoking and BB use were associated with repeat PCI (OR: 1.48 and 1.56, respectively). CONCLUSIONS: After PCI, patients with DM alone have higher mortality compared to patients without DM and hypertension, with both DM and hypertension, and with hypertension alone. Comorbid hypertension does not appear to increase risk in DM patients, whereas comorbid DM appears to increase risk in hypertensive patients. TRIAL REGISTRATION: REC103-15 IRB of Taichung Tzu-chi Hospital.

Activation of corticostriatal circuitry relieves chronic neuropathic pain.

Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation.

AMPAkines Target the Nucleus Accumbens to Relieve Postoperative Pain.

BACKGROUND: AMPAkines augment the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the brain to increase excitatory outputs. These drugs are known to relieve persistent pain. However, their role in acute pain is unknown. Furthermore, a specific molecular and anatomic target for these novel analgesics remains elusive. METHODS: The authors studied the analgesic role of an AMPAkine, CX546, in a rat paw incision (PI) model of acute postoperative pain. The authors measured the effect of AMPAkines on sensory and depressive symptoms of pain using mechanical hypersensitivity and forced swim tests. The authors asked whether AMPA receptors in the nucleus accumbens (NAc), a key node in the brain's reward and pain circuitry, can be a target for AMPAkine analgesia. RESULTS: Systemic administration of CX546 (n = 13), compared with control (n = 13), reduced mechanical hypersensitivity (50% withdrawal threshold of 6.05 ± 1.30 g [mean ± SEM] vs. 0.62 ± 0.13 g), and it reduced depressive features of pain by decreasing immobility on the forced swim test in PI-treated rats (89.0 ± 15.5 vs. 156.7 ± 18.5 s). Meanwhile, CX546 delivered locally into the NAc provided pain-relieving effects in both PI (50% withdrawal threshold of 6.81 ± 1.91 vs. 0.50 ± 0.03 g; control, n = 6; CX546, n = 8) and persistent postoperative pain (spared nerve injury) models (50% withdrawal threshold of 3.85 ± 1.23 vs. 0.45 ± 0.00 g; control, n = 7; CX546, n = 11). Blocking AMPA receptors in the NAc with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione inhibited these pain-relieving effects (50% withdrawal threshold of 7.18 ± 1.52 vs. 1.59 ± 0.66 g; n = 8 for PI groups; 10.70 ± 3.45 vs. 1.39 ± 0.88 g; n = 4 for spared nerve injury groups). CONCLUSIONS: AMPAkines relieve postoperative pain by acting through AMPA receptors in the NAc.

Association between statin therapy and long-term clinical outcomes in patients with stable coronary disease undergoing percutaneous coronary intervention.

This longitudinal cohort study examined the long-term effect of statin therapy on clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). A total of 1760 patients with stable coronary artery disease (CAD) were divided by receipt of statin therapy or not after index PCI. Baseline clinical characteristics, risk factors, angiographic findings, and medications after interventional procedure were assessed to compare long-term clinical outcomes between groups. Predictors for all-cause death and major adverse cardiovascular events (MACE), including myocardial infarction (MI), cardiovascular death, and repeated PCI procedures, were also analyzed. The statin therapy group had higher average serum cholesterol and more elevated low-density lipoprotein cholesterol (LDL-C) than the non-statin therapy group (189.0 ± 47.9 vs 169.3 ± 37.00 mg/dl, 117.2 ± 42.6 vs 98.7 ± 31.8 mg/dl, respectively, both P < 0.001). The non-statin group had higher rates of all-cause death and cardiovascular death compared to statin group (both P < 0.001). After adjustment for age, diabetes, and chronic kidney disease, Cox proportion hazard analysis revealed statin use significantly reduced all-cause death and repeated PCI procedure (hazard ratio: 0.53 and 0.69, respectively). Statin use seemed not reduce the hazard of cardiovascular death or MI in patients with stable CAD after PCI; however, statin therapy still was associated with reduced rates of all-cause death and repeat PCI procedure.

Design and Study of a Portable High-frequency Ventilator for Clinical Applications.

Treatment costs for ventilator-dependent patients are a substantial burden not only for their family but also for medical systems in general. Recently, using high-frequency ventilators have been shown to reduce the risk of lung injury through low-volume airflow. However, the machines used today remain bulky, costly, and only for use in hospital settings. To provide intermediate therapy for patients between hospitalization and complete discharge, a portable, light-weight high-frequency ventilator is an urgent need. This work presents the design of a portable high-frequency ventilator and a study of its practicality for further clinical medical applications. Through the integration of advanced electronics and mechanical instruments, we develop a portable high-frequency ventilator with reconfigurable oxygen flow rate, applied pressure, and air volume for the needs of individual patients. A miniaturized portable high-frequency ventilator with digital controller and feedback system for stabilization and precision control is implemented. The efficiency of CO2 washout using the proposed ventilator has been demonstrated in animal trials.

Vacuolar serine protease is a major allergen of Cladosporium cladosporioides.

BACKGROUND: Cladosporium is an important allergenic fungus worldwide. We report here a major allergen of C. cladosporioides. METHODS: Major C. cladosporioides allergens were characterized by immunoblotting, N-terminal amino acid sequencing, protein purification and cDNA cloning. RESULTS: Seventy-four sera (38%) from 197 bronchial asthmatic patients demonstrated IgE binding against C. cladosporioides extracts. Among these 74 sera, 41 (55%) and 38 (51%) showed IgE binding against a 36- and a 20-kDa protein of C. cladosporioides, respectively. Both IgE-reacting components reacted with FUM20, a monoclonal antibody against fungal serine proteases. N-terminal amino acid sequencing results suggest that they are vacuolar serine proteases, and the 20-kDa component is possibly a degraded product of the 36-kDa allergen. A corresponding 5'-truncated 1,425-bp cDNA fragment was isolated. The mature protein after N-terminal processing starts with an N-terminal serine that is the ninth residue encoded by the 5'-truncated cDNA. The protein sequence deduced shares 69-72% sequence identity with Penicillium vacuolar serine proteases and was designated as Cla c 9. The purified 36-kDa Cla c 9 allergen showed proteolytic activity with peptide Z-Ala-Ala-Leu-pNA as substrate. IgE cross-reactivity was detected between the purified Cla c 9 and serine protease allergens from Aspergillusfumigatus and Penicillium chrysogenum. CONCLUSION: We identified a vacuolar serine protease as a major allergen of C. cladosporioides (Cla c 9) and a major pan-allergen of prevalent airborne fungi. IgE cross-reactivity among these highly conserved serine protease pan-fungal allergens was also detectable.

Prognostic Analysis for Cardiogenic Shock in Patients with Acute Myocardial Infarction Receiving Percutaneous Coronary Intervention.

Cardiogenic shock (CS) is uncommon in patients suffering from acute myocardial infarction (AMI). Long-term outcome and adverse predictors for outcomes in AMI patients with CS receiving percutaneous coronary interventions (PCI) are unclear. A total of 482 AMI patients who received PCI were collected, including 53 CS and 429 non-CS. Predictors for AMI patients with CS including recurrent MI, cardiovascular (CV) mortality, all-cause mortality, and repeated-PCI were analyzed. The CS group had a lower central systolic pressure and central diastolic pressure (both P < 0.001). AMI patients with hypertension history were less prone to develop CS (P < 0.001). Calcium channel blockers and statins were less frequently used by the CS group than the non-CS group (both P < 0.05) after discharge. Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score, CV mortality, and all-cause mortality were higher in the CS group than the non-CS group (all P < 0.005). For patients with CS, stroke history was a predictor of recurrent MI (P = 0.036). CS, age, SYNTAX score, and diabetes were predictors of CV mortality (all P < 0.05). CS, age, SYNTAX score, and stroke history were predictors for all-cause mortality (all P < 0.05). CS, age, and current smoking were predictors for repeated-PCI (all P < 0.05).

Prognostic Significance of Central Pulse Pressure for Mortality in Patients With Coronary Artery Disease Receiving Repeated Percutaneous Coronary Intervention.

Coronary artery disease (CAD) is a life-threatening medical emergency which needs urgent medical attention. Percutaneous coronary intervention (PCI) is common and necessary for patients with CAD, but it has not completely evaluated in cases with repeated PCI. Therefore, the aim of this study was to examine the risk factors and prognosis in patients with CAD requiring repeated PCI. This is a prospective observational study. A total of 1126 patients with CAD requiring PCI took part in this study. Clinical parameters including baseline characteristics, hemodynamic data, location of vascular lesions, SYNTAX score, left ventricular ejection fraction, central pulse pressure (CPP), central aortic systolic pressure (CSP), risk factors, and invasive strategies were analyzed to identify the risk factors for patients requiring repeated PCI. We further analyzed the prognosis, including risk for myocardial infarction (MI), cardiovascular (CV) mortality, and all-cause mortality, in patients with repeated PCI. Among patients with PCI, 276 received repeated PCI. Patients in the repeated PCI group had a higher CPP (66.7 vs 62.5 mm Hg; P = 0.006), CSP (139.9 vs 135.9 mm Hg; P = 0.017), and male preponderance (P = 0.012). Drugs including diuretics, beta-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), and aspirin were all used more frequently in the repeated PCI group (all P < 0.05). Freedom from MI was lower in the repeated PCI group than in the single PCI group (P < 0.001). Logistic regression revealed that CPP, CSP, number of diseased vessels, male sex, usage of diuretics, BBs, ACEIs, and MI were all predictors for requiring repeated PCI (all P < 0.05). In addition, CPP was a predictor for MI attack, CV mortality, and all-cause mortality in the repeated PCI group (P = 0.010, P = 0.041, P = 0.004, respectively). Elevated CPP, CSP, male sex, multiple diseased vessels, and the usage of diuretics, BBs, ACEIs, and MI were predictors for repeated PCI. Most importantly, CPP was strongly associated with MI attack, CV mortality, and all-cause mortality, and could serve as a prognostic parameter for mortality in patients with CAD after performing repeated PCI.

Persistent neuropathic pain increases synaptic GluA1 subunit levels in core and shell subregions of the nucleus accumbens.

The nucleus accumbens (NAc) is a key component of the brain reward system, and it is composed of core and shell subregions. Glutamate transmission through AMPA-type receptors in both core and shell of the NAc has been shown to regulate reward- and aversion-type behaviors. Previous studies have additionally demonstrated a role for AMPA receptor signaling in the NAc in chronic pain states. Here, we show that persistent neuropathic pain, modeled by spared nerve injury (SNI), selectively increases the numbers of GluA1 subunits of AMPA receptors at the synapse of both core and shell subregions. Such increases are not observed, however, for the GluA2 subunits. Furthermore, we find that phosphorylation at Ser845-GluA1 is increased by SNI at both core and shell subregions. These results demonstrate that persistent neuropathic pain increases AMPA receptor delivery to the synapse in both NAc core and shell, implying a role for AMPA receptor signaling in these regions in pain states.

Persistent pain alters AMPA receptor subunit levels in the nucleus accumbens.

BACKGROUND: A variety of pain conditions have been found to be associated with depressed mood in clinical studies. Depression-like behaviors have also been described in animal models of persistent or chronic pain. In rodent chronic neuropathic pain models, elevated levels of GluA1 subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the nucleus accumbens (NAc) have been found to inhibit depressive symptoms. However, the effect of reversible post-surgical pain or inflammatory pain on affective behaviors such as depression has not been well characterized in animal models. Neither is it known what time frame is required to elicit AMPA receptor subunit changes in the NAc in various pain conditions. RESULTS: In this study, we compared behavioral and biochemical changes in three pain models: the paw incision (PI) model for post-incisional pain, the Complete Freund's Adjuvant (CFA) model for persistent but reversible inflammatory pain, and the spared nerve injury (SNI) model for chronic postoperative neuropathic pain. In all three models, rats developed depressive symptoms that were concurrent with the presentation of sensory allodynia. GluA1 levels at the synapses of the NAc, however, differed in these three models. The level of GluA1 subunits of AMPA-type receptors at NAc synapses was not altered in the PI model. GluA1 levels were elevated in the CFA model after a period (7 d) of persistent pain, leading to the formation of GluA2-lacking AMPA receptors. As pain symptoms began to resolve, however, GluA1 levels returned to baseline. Meanwhile, in the SNI model, in which pain persisted beyond 14 days, GluA1 levels began to rise after pain became persistent and remained elevated. In addition, we found that blocking GluA2-lacking AMPA receptors in the NAc further decreased the depressive symptoms only in persistent pain models. CONCLUSION: Our study shows that while both short-term and persistent pain can trigger depression-like behaviors, GluA1 upregulation in the NAc likely represents a unique adaptive response to minimize depressive symptoms in persistent pain states.

Lys, pro and trp are critical core amino acid residues recognized by FUM20, a monoclonal antibody against serine protease pan-fungal allergens.

BACKGROUND: Alkaline/vacuolar serine proteases comprise a major group of pan-fungal allergens from several prevalent airborne fungal species. It is of importance to characterize antigenic determinant(s) recognized by monoclonal antibodies against these major allergens. METHODS: The antigenic determinant of fungal serine proteases recognized by a monoclonal antibody, FUM20, was analyzed by dot immunoassay of synthetic peptides immobilized on cellulose membrane. Results obtained were confirmed by wild-type recombinant protease and its mutants. The epitopes were mapped to the structure of serine proteases by molecular modeling. RESULTS: A linear epitope encompassing 9 amino acids from Pen ch 18 ((6)EKNAPWGLA(14)) binds FUM20. The corresponding peptide ((5)AKGAPWGLA(13)) from Rho m 2 also binds FUM20. Substitution of K6, P9 or W10 with alanine in this peptide resulted in drastic loss of FUM20 binding. Rho m 2 mutants with single K6A, P9A, P9G, W10A or W10F substitute showed negative immunoblot reactivity against FUM20. However, the Rho m 2 K6R mutant can bind FUM20. Three-dimensional structural models of the FUM20 antigenic determinants on serine proteases were constructed. The lysine residue critical for FUM20 interaction is on the surface of the proteases and solvent accessible. The critical core residue proline is located at the beginning of an alpha-helix. CONCLUSIONS: The lysine, proline and tryptophan residues located on the N-terminal region of fungal serine proteases are critical core amino acid residues recognized by FUM20, a monoclonal antibody against serine protease pan-fungal allergens. These findings advance our understanding of the antigenic structures responsible for the antigenicity of serine protease allergens.