The exercise pressor reflex: An update

The exercise pressor reflex is a feedback mechanism engaged upon stimulation of mechano- and metabosensitive skeletal muscle afferents. Activation of these afferents elicits a reflex increase in heart rate, blood pressure, and ventilation in an intensity-dependent manner. Consequently, the exercise pressor reflex has been postulated to be one of the principal mediators of the cardiorespiratory responses to exercise. In this updated review, we will discuss classical and recent advancements in our understating of the exercise pressor reflex function in both human and animal models. Particular attention will be paid to the afferent mechanisms and pathways involved during its activation, its effects on different target organs, its potential role in the abnormal cardiovascular response to exercise in diseased states, and the impact of age and biological sex on these responses. Finally, we will highlight some unanswered questions in the literature that may inspire future investigations in the field.

     

In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A^131R-chimeric receptor (CR), and those engineered with the low-affinity CD16^158F-CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A^131R-CR T cells was 74 ± 10%, whereas the percentage of CD16^158F-CR T cells was 46 ± 15%. Only CD32A^131R-CR T cells bound panitumumab. CD32A^131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16^158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116^FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A^131R-CR on T cells by cetuximab or panitumumab and CD16^158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A^131R-CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR.     

The diagnostic usefulness of the combined COMPASS 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy

The study investigated the diagnostic performance for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of composite autonomic symptom score (COMPASS) 31, validated questionnaire for autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed for detecting DPN and CAN. One‐hundred and two participants with diabetes (age 57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC), and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN (≥ 1 abnormal CART) and confirmed CAN (≥ 2 abnormal CARTs) were present in 28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in 52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal ESC (hands ESC <50 μS and/or feet ESC <70 μS) in 47.4%. Both the patterns—COMPASS 31+ESC and COMPASS 31 and/or ESC—were associated with CAN and DPN (P < .01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN. The combination of the tests can allow a stepwise screening strategy for CAN, by suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality.     

Aesthetics in oral implantology: biological, clinical, surgical, and prosthetic aspects

OBJECTIVES: The aim of this study was to identify a correct clinical, surgical, and prosthetic management of endosseous implants replacing missing teeth in the anterior maxilla, achieving predictable aesthetic outcomes. Placement of immediate post-extraction implants without incisions or flap elevation is one of the surgical treatment options able to improve the healing and regenerative potentials of the fresh socket. MATERIALS: Fifty-five patients (33 men, 22 women), ranging in age from 19 to 57 years (mean 29), were selected for this study. All the patients were not smokers, no bruxers, presented stable soft tissue conditions, an acceptable occlusion, and the absence of pathologies that would contraindicate bone healing. Patients were treated with implants made by 2 manufacturers: Institute Straumann, Walderburg, Switzerland and Friadent, Mannheim, Germany. A total of 87 implants were placed immediately after each failing tooth had been removed. The temporary restoration was placed 3 months after implant placement, and the final restoration was placed 4 months from the surgical procedure. The patients were evaluated clinically and radiographically at implant placement, and 2, 4, 18, and 24 months post-insertion. RESULTS: At 24 months, only 3 implants were lost (2 in male patients;1 in female patient). All of these failed implants did not achieve osseointegration. The overall success rate was 96.6%, with an implant failure rate of 3.4%, all prior to restoration. CONCLUSIONS: The immediate placement in the anterior maxilla fresh extraction sockets without incisions or flaps elevation is a surgical option that can ensure ideal peri-implant tissues healing, preserving the presurgical gingival and bone aspects. For a predictable aesthetic result, the most important aspect seems to be the height and thickness of the buccal bone wall, which remain after immediate placement of the fixture.     

Microsatellite and RAS/RAF Mutational Status as Prognostic Factors in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

Background

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS.

Methods

Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS).

Results

The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4–51.2 months], and the median DFS was 13.6 months (95% CI, 12.3–14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4–24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS.

Conclusion

For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.

     

Hypercoagulability markers in young asymptomatic heterozygous carriers of factor V Leiden (G1691A) or prothrombin (G20210A) variant

BACKGROUND: Mutations in factor V (factor V Leiden-G1691A) and prothrombin (G20210A) genes are important risk factors for thrombophilia due to their high incidence in patients with thromboembolic events, especially among the young. However, it is not clear if levels of hypercoagulability markers are significantly altered in asymptomatic young carriers of factor V Leiden or prothrombin G20210A. METHODS: Hemostatic status of 32 asymptomatic young individuals carrying these mutations and of 18 normal control individuals was investigated through the determination of plasma thrombomodulin (TM), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and D-dimer. RESULTS: No significant differences were observed in these hemostatic markers when comparing groups of individuals carrying mutations and the control group. CONCLUSION: Analysis of these results leads to the conclusion that the presence of these mutations, in the absence of acquired risk factors, does not constantly predispose these young carriers to a state of hypercoagulability.     

Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha

Activation of inflammatory pathways may contribute to the beginning and the progression of both atherosclerosis and type 2 diabetes. Here we report a novel interaction between insulin action and control of inflammation, resulting in glucose intolerance and vascular inflammation and amenable to therapeutic modulation. In insulin receptor heterozygous (Insr+/-) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-alpha-converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity. Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation. Double heterozygous Insr+/-Timp3+/- mice develop mild hyperglycemia and hyperinsulinemia at 3 months and overt glucose intolerance and hyperinsulinemia at 6 months. A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/- diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/- mice compared with WT mice. Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation.     

Management of acute urinary retention: a worldwide survey of 6074 men with benign prostatic hyperplasia

Study Type – Therapy (symptom prevalence) Level of Evidence 2a What's known on the subject? and What does the study add? Largest survey ever conducted evaluating the management of AUR in real life practice in a wide range of health care systems. It shows that urethral catheterization followed by a TWOC has become a standard worldwide and that α₁‐blockade prior to TWOC doubles the chances of success. It also evidences important differences (hospitalization rate, duration of catheterization ...) between countries/regions reflecting lack of guidelines. This large survey also clearly identifies predictors of TWOC failure.

OBJECTIVES

• ? To evaluate the management of acute urinary retention (AUR) associated with benign prostatic hyperplasia (BPH) in real‐life practice.
• ? To identify predictors of successful trial without catheter (TWOC).

MATERIALS AND METHODS

• ? In all, 6074 men catheterized for painful AUR were enrolled in a prospective, cross‐sectional survey conducted in public and private urology practices in France, Asia, Latin America, Algeria and the Middle East.
• ? Patient clinical characteristics, type of AUR and its management (type of catheterization, hospitalization, TWOC, use of α₁‐blockers, immediate or elective surgery) and adverse events observed during the catheterization period were recorded.
• ? Predictors of TWOC success were also analysed by multivariate regression analysis with stepwise procedure.

RESULTS

• ? Of the 6074 men, 4289 (71%) had a spontaneous AUR and 1785 (29%) had a precipitated AUR, mainly as the result of loco‐regional/general anaesthesia (28.5%) and excessive alcohol intake (18.2%).
• ? Presence of BPH was revealed by AUR in 44% of men. Hospitalization for AUR varied between countries, ranging from 1.7% in Algeria to 100% in France. A urethral catheter was inserted in most cases (89.8%) usually followed by a TWOC (78.0%) after a median of 5 days. Overall TWOC success rate was 61%.
• ? Most men (86%) received an α₁‐blocker (mainly alfuzosin) before catheter removal with consistently higher TWOC success rates, regardless of age and type of AUR. Multivariate regression analysis confirmed that α₁‐blocker before TWOC doubled the chances of success (odds ratio 1.92, 95% CI 1.52–2.42, P < 0.001).
• ? Age ≥70 years, prostate size ≥50 g, severe lower urinary tract symptoms, drained volume at catheterization ≥1000 mL and spontaneous AUR favoured TWOC failure. Catheterization >3 days did not influence TWOC success but was associated with increased morbidity and prolonged hospitalization for adverse events.
• ? In the case of TWOC failure, 49% of men were recatheterized and had BPH surgery and 43.5% tried another TWOC with a success rate of 29.5%. Elective surgery was preferred to immediate surgery.

CONCLUSIONS

• ? TWOC has become a standard practice worldwide for men with BPH and AUR.
• ? In most cases, an α₁‐blocker is prescribed before TWOC and significantly increases the chance of success.
• ? Prolonged catheterization is associated with an increased morbidity.

     

Efficacy and safety profile of a novel technique,ThuLEP (Thulium laser enucleation of the prostate) for the treatment of benign prostate hypertrophy. Our experience on 148 patients

Background

Over the past years laser technology has played a predominant role in prostate surgery, for the treatment of benign prostate hypertrophy (BPH). Various laser devices have been introduced in clinical practice, showing good results in terms of complications and urodynamic outcomes efficacy compared with TURP and Open Prostatectomy.

In this study we describe the efficacy and the safety profile of a novel laser technique, ThuLEP (Thulium Laser Enucleation of Prostate) that permits a complete anatomical endoscopic enucleation of prostatic adenoma independently to prostate size.

Methods

148 patients with a mean age of 68.2 years were enrolled between September 2009 and March 2012 (36 months), and treated for BPH with ThuLEP. Every patient was evaluated at base line according to: Digital Rectal Examination (DRE), prostate volume, Post-Voided volume (PVR), International Prostate Symptoms Score (I-PSS), International Index of Erectile Function-5 (IIEF-5), Quality of Life (QoL), PSA values, urine analysis and urine culture, uroflowmetry. The same evaluation was conducted after a 12 month follow-up. ThuLEP was performed by 2 expert surgeons.

Results

Our data showed a better post-operative outcome in terms of catheter removal, blood loss, TURP syndrome, clot retention and residual tissue compared to large series of TURP and OP. Only 1.3% of patients had bladder wall injury during morcellation. I-PSS, Qmax, Prostate Volume, QoL and PVR showed a highly significant improvement at 12 month follow-up in comparison to preoperative assessment.

Conclusion

ThuLEP represent an innovative option in patients with BPH. It is a size independent surgical endoscopic technique and it can be considered the real alternative, at this time, to TURP and even more to Open Prostatectomy for large prostate, with a complete removal of adenoma and with a low complication rate.