Comparison of the positive inotropic effects of serotonin,histamine, angiotensin II,endothelin and isoprenaline in the isolated human right atrium

Summary The receptor systems through which serotonin (5-HT), histamine, angiotensin II and endothelin increase the force of contraction were studied in isolated right atria from patients without apparent heart failure.All agonists increased the atrial force of contraction in a concentration-dependent manner; maximal effects, however, were significantly less than those evoked by isoprenaline or Ca²⁺. 5-HT and histamine, but not angiotensin II and endothelin, activated adenylate cyclase, whereas endothelin and angiotensin II stimulated inositol phosphate generation. Experiments with subtype-selective antagonists revealed that histamine effects were mediated by H₂-receptors (sensitive to ranitidine), 5-HT-effects by 5-HT₄-receptors (sensitive to SDZ 205-557) and angiotensin II effects by AT₁-receptors (sensitive to losartan).We conclude that in human right atria the force of contraction can be increased by cyclic AMP-dependent (histamine, 5-HT) and -independent (angiotensin II, endothelin) pathways. Compared to -adrenoceptors, however, all other receptor systems increase the force of contraction only submaximally indicating that the -adrenoceptor pathway is the most important physiological mechanism to regulate force of contraction and/or heart rate in the human heart.Correspondence to O. E. Brodde at the above address     

Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection

Host cell proteases such as TMPRSS2 are critical determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion. Consequently, AT blocks entry driven by the Spikes of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and its variants of concern including Omicron, and suppresses lung cell infection with genuine SARS-CoV-2. Thus, AT is an endogenous inhibitor of SARS-CoV-2 that may be involved in COVID-19 pathogenesis. We further demonstrate that activation of AT by anticoagulants, such as heparin or fondaparinux, increases the anti-TMPRSS2 and anti-SARS-CoV-2 activity of AT, suggesting that repurposing of native and activated AT for COVID-19 treatment should be explored.     

Neutral oligosaccharide content of preterm human milk

Human milk oligosaccharides are known to play a role in protection against certain infectious diseases. Previous reports indicate that the content of human milk oligosaccharides varies widely among individuals at term but such information on preterm milk is lacking. After removal of the fat, protein and most of the lactose from non-pooled human milk samples, a total neutral oligosaccharide fraction was isolated by ion-exchange chromatography followed by gel filtration. A Dionex high-performance anion-exchange chromatography system equipped with a pulsed electrometric detector was then employed to measure the levels of ten neutral oligosaccharides in the individual milk samples. Twenty-three milk samples from thirteen mothers who delivered at a mean gestational age of 29.5 (SD 3.1) weeks were collected between days 0 and 33 of lactation, and compared with three samples of term milk from two mothers. The ranges of the total and individual levels of the ten neutral oligosaccharides in preterm milk were similar to those in term milk. Further, as previously described in term milk, preterm milk exhibited a quantitative individual variation. This variation was independent of the gestational age, day of lactation, and postconceptional age. In conclusion, levels of ten neutral oligosaccharides did not differ between preterm and term human milk.     

Effects of RSR13, a synthetic allosteric modifier of hemoglobin, alone and in combination with dizocilpine, on outcome from transient focal cerebral ischemia in the rat

This study examined the effect of a pharmacologically induced rightward shift in the partial pressure of oxygen at which 50% of hemoglobin is saturated (P50) on outcome from transient focal cerebral ischemia in the rat. Halothane anesthetized rats (n=20 per group) were given saline or a single 15-min infusion of 150 mg/kg RSR13 (2-[4-[[3,5-dimethylanilino) carbonyl]methyl]phenoxy]-2-methylproprionic acid) intravenously before or 30 min after onset of 75 min of middle cerebral artery filament occlusion (MCAO). Seven days later, severity of hemiparesis and cerebral infarct size were examined. RSR13 alone did not significantly improve outcome. Conscious normothermic rats (n=12 per group) were also given RSR13 (150 mg/kg) or 0.9% NaCl intravenously and subjected to 75 min of MCAO with 7 days of recovery. Again, RSR13 alone did not significantly reduce infarct size or improve neurologic score. A dose-response curve for dizocilpine (MK-801) was then constructed in conscious normothermic rats subjected to 75 min of MCAO. Dizocilpine (0.5 mg/kg i.v.) caused a 90% reduction in mean infarct size while 0.25 mg/kg reduced infarct size by 48%. Other rats were then subjected to 75 min of MCAO after being given dizocilpine (0.25 mg/kg i.v.; n=18) or RSR13 (150 mg/kg i.v. )+dizocilpine (0.25 mg/kg i.v.; n=15). RSR13+dizocilpine resulted in smaller cortical infarct volume (8+/-14 mm3 vs. 34+/-37 mm3, p<0.02) and total cerebral infarct volume (46+/-28 mm3 vs. 81+/-60 mm3, p<0. 05) compared to dizocilpine alone, respectively. We conclude that a pre-ischemic peak increase in P50 of approximately 25 mmHg alone is insufficient to reduce focal ischemic injury, but may be advantageous when used in conjunction with other neuroprotective agents.     

Satisfaction with nursing homes. The design of employees' jobs can ultimately influence family members' perspectives

Organizational commitment on the part of nursing home employees can be a determinant of service quality. Proper design of health care jobs and clarity of roles make employees feel more dedicated to their jobs, enable them to do their jobs well, and enhance family members' evaluations of nursing home care. When management develops a dynamic, interactive, high-quality environment, nursing home employees feel encouraged to report shortcomings without fear because they are involved in the process.     

Segmental stability and compressive strength of posterior lumbar interbody fusion implants

STUDY DESIGN: Human cadaveric study on initial segmental stability and compressive strength of posterior lumbar interbody fusion implants. OBJECTIVES: To compare the initial segmental stability and compressive strength of a posterior lumbar interbody fusion construct using a new cortical bone spacer machined from allograft to that of titanium threaded and nonthreaded posterior lumbar interbody fusion cages, tested as stand-alone and with supplemental pedicle screw fixation. SUMMARY OF BACKGROUND DATA: Cages were introduced to overcome the limitations of conventional allografts. Radiodense cage materials impede radiographic assessment of the fusion, however, and may cause stress shielding of the graft. METHODS: Multisegmental specimens were tested intact, with posterior lumbar interbody fusion implants inserted into the L4/L5 interbody space and with supplemental pedicle screw fixation. Three posterior lumbar interbody fusion implant constructs (Ray Threaded Fusion Cage, Contact Fusion Cage, and PLIF Allograft Spacer) were tested nondestructively in axial rotation, flexion-extension, and lateral bending. The implant-specimen constructs then were isolated and compressed to failure. Changes in the neutral zone, range of motion, yield strength, and ultimate compressive strength were analyzed. RESULTS: None of the stand-alone implant constructs reduced the neutral zone. Supplemental pedicle screw fixation decreased the neutral zone in flexion-extension and lateral bending. Stand-alone implant constructs decreased the range of motion in flexion and lateral bending. Differences in the range of motion between stand-alone cage constructs were found in flexion and extension (marginally significant). Supplemental posterior fixation further decreased the range of motion in all loading directions with no differences between implant constructs. The Contact Fusion Cage and PLIF Allograft Spacer constructs had a higher ultimate compressive strength than the Ray Threaded Fusion Cage. CONCLUSIONS: The biomechanical data did not suggest any implant construct to behave superiorly either as a stand-alone or with supplemental posterior fixation. The PLIF Allograph Spacer is biomechanically equivalent to titanium cages but is devoid of the deficiencies associated with other cage technologies. Therefore, the PLIF Allograft Spacer is a valid alternative to conventional cages.     

Effect of implant design and endplate preparation on the compressive strength of interbody fusion constructs

STUDY DESIGN: A human cadaveric study on the compressive strength of different lumbar interbody fusion implants and endplate preparation techniques was performed. OBJECTIVES: To assess the axial compressive strength of an implant with peripheral endplate contact as opposed to full surface contact, and to assess whether removal of the central bony endplate affects the axial compressive strength. SUMMARY OF BACKGROUND DATA: The compressive strength of interbody fusion constructs has been compared between implants and bone grafts. Neither implant design nor endplate preparation has been shown to affect strength. Removal of the central bony endplate for bone grafts was noted to improve graft incorporation but also to facilitate subsidence. METHODS: A total of 44 vertebrae were tested in four experimental groups by combining two interbody implants (full-surface vs peripheral surface support) with two endplate preparation techniques (intact bony endplate vs removal of the central bony endplate). Specimens were tested to ultimate compressive failure using a 50 N/second ramped load. Yield strength and ultimate compressive strength were compared between groups using two-factor analysis of covariance. A P value less than 0.05 was considered significant. Stepwise linear regressions assessed the predictive power of age, bone mineral content, and the implant's normalized endplate coverage on yield strength and ultimate compressive strength. RESULTS: Neither implant design nor endplate preparation technique affected yield strength or ultimate compressive strength. Age, bone mineral content, and the normalized endplate coverage were strong predictors of yield strength (P < 0. 0001; r2 = 0.459) and ultimate compressive strength (P < 0.0001; r2 = 0.510). CONCLUSIONS: An implant with only peripheral support resting on the apophyseal ring offers axial mechanical strength similar to that of an implant with full support. Neither supplementary struts nor a solid implant face has any additional mechanical advantage, but reduces graft-host contact area. Removal of the central bony endplate is recommended because it does not affect the compressive strength and promotes graft incorporation.     

Local anaesthetic injection with and without corticosteroids for subacromial impingement syndrome

Fifty patients with impingement syndrome refractory to long-term conservative treatment were randomized to three treatment groups. All patients received an injection of 10 ml 0.5% bupivacaine, in group 1 without corticosteroid, in group 2 with crystalline corticosteroid and in group 3 with lipoid corticosteroid. Treatment in group 1 had to be stopped because of inefficacy. In groups 2 and 3 favorable results were achieved in 19 out of 40 patients.

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Résumé  50 patients avec conflit sous-aeromial, qui ne montraient pas d’amélioration après un long traitement conservatif récevaient une injection dans la bourse subacromiale. Le premier groupe récevait une injection contenant un anaesthétique local pur, groupe 2 une mixture d’anaesthétique avec des corticostéroides cristalins et groupe 3 avec des corticostéroides lipoides. Le traitement du groupe 1 devait être arrété cause d’inificacité. 19 de 40 patients du groupe 2 et 3 montraient une amélioration après 6 mois.

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Accepted: 6 January 2000     

Diagnostic accuracy of the palliative prognostic score in hospitalized patients with advanced cancer.

PURPOSE: To evaluate the predictive accuracy of the Palliative Prognostic (PaP) score in patients with advanced cancer under the care of an oncologist. PATIENTS AND METHODS: The PaP score was calculated in 100 consecutive patients with advanced cancer hospitalized under the care of a medical or radiation oncologist at a university teaching hospital in Australia. The attending oncologist predicted the survival duration for the purpose of the scoring. The positive predictive value of the PaP score was evaluated. Survival analysis was performed to compare the survival of the three prognostic groups. RESULTS: Assessable survival data were available for 98 patients. The overall median survival was 12 weeks (interquartile range, 7 to 25 weeks). The PaP score divided the heterogeneous patient sample into three isoprognostic groups related to the chance of surviving 1 month, with 64 patients in group A (> 70% chance), 32 patients in group B (30% to 70% chance), and four patients in group C (< 30% chance). The estimated median survival of the three groups was 17 weeks (95% CI, 12 to 26 weeks), 7 weeks (95% CI, 4 to 12 weeks), and less than 1 week (95% CI, < 1 to 3 weeks), respectively. These survival differences were highly significant (log-rank test of trend, chi1(2) = 25.65; P < .0001). The 1-month survival of the groups was 97%, 59%, and 25%, respectively. CONCLUSION: When oncologists' survival estimates are used, the PaP score is able to identify accurately three isoprognostic patient groups, irrespective of the cancer type. The PaP score may help reduce the uncertainty of formulating a prognosis in patients with advanced cancer.