CO2-related vasoconstriction superimposed on ischemic medullary brain autonomic nuclei may contribute to sudden death

Introduction: In 2015, a multinational randomized controlled phase IV clinical trial of adaptive servoventilation for the management of heart failure with central sleep apnea was halted in progress because more patients in the study group were dying than in the control group. One year later, another large clinical trial reported results on the effectiveness of continuous positive airway pressure (CPAP) in preventing sudden death and other cardiovascular events such as heart attack and stroke in patients with preexisting vascular disease as well as obstructive sleep apnea. Background: Sudden unexpected death has been associated with many types of small and nonmalignant medullary brain lesions, like demyelination plaques \u2014 largely asymptomatic until they caused sudden death. Many such medullary lesions, typically without hemorrhage or mass effect, have in themselves been previously considered relatively harmless \u2014 in cases where they have been known to be present. Discussion: Why did not the improved pulmonary ventilation and subsequently improved gas exchange provided during the CPAP and servoventilation clinical trials help to resolve any ischemic lesions that may have been present both in the heart and in the medulla, thereby tending to normalize interactions between the vagal neural structures and the heart? CO2 is a potent dilator of brain vasculature, thereby increasing blood flow to the brain. When ventilation is increased, even if only to improve it back toward normal from a depressed steady-state level, the alveolar partial pressure of carbon dioxide is decreased, likely resulting in a converse relative vasoconstriction in the brain, thereby reducing blood flow in the brain, especially in watershed areas like the solitary tract nucleus. In normal physiology, this is demonstrated impressively by the ability of hyperventilation to induce loss of consciousness. Conclusions: The findings of several clinical trials recently reported, taken together with neuropathology case studies reported elsewhere, suggest that additional research is warranted in regard to the mechanisms by which focal medullary autonomic brain ischemia may be related to sudden death in general medical illnesses \u2014 and how it may additionally be influenced by changes in arterial CO2 levels

Sacituzumab govitecan in metastatic triple-negative breast cancer

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan

The origins and spread of domestic horses from the Western Eurasian steppes

Analysis of 273 ancient horse genomes reveals that modern domestic horses originated in the Western Eurasian steppes, especially the lower Volga-Don region.Domestication of horses fundamentally transformed long-range mobility and warfare(1). However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling(2-4) at Botai, Central Asia around 3500 bc(3). Other longstanding candidate regions for horse domestication, such as Iberia(5) and Anatolia(6), have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association(7) between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc(8,9) driving the spread of Indo-European languages(10). This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture(11,12).Descriptive and Comparative Linguistic

The origins and spread of domestic horses from the Western Eurasian steppes

Domestication of horses fundamentally transformed long-range mobility and warfare. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling at Botai, Central Asia around 3500 bc. Other longstanding candidate regions for horse domestication, such as Iberia and Anatolia, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc driving the spread of Indo-European languages. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture

Anterior mandibular apical base augmentation in the surgical orthodontic treatment of mandibular retrusion

The authors describe a surgical technique alternative to traditional pre-surgical orthodontics in order to increase the apical base in mandibular retrusion (class II, division I). This subapical osteotomy, optimizing inferior incisal axis without dental extractions and a long orthodontic treatment, associated to genioplasty permits to obtain an ideal labio-dento-mental morphology. This procedure avoids in some cases the need of a mandibular advancement and, if necessary, it reduces his entity with obvious advantages.(copyright) 2005 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved