Asymmetrical nasal high flow ventilation improves clearance of CO2 from the anatomical dead space and increases positive airway pressure.

Positive airway pressure that dynamically changes with breathing, and clearance of anatomical dead space are the key mechanisms of noninvasive respiratory support with nasal high flow (NHF). Pressure mainly depends on flow rate and nare occlusion. The hypothesis is that an increase in asymmetrical occlusion of the nares leads to an improvement in dead-space clearance resulting in a reduction in re-breathing. Clearance was investigated with volumetric capnography in an adult upper-airway model, which was ventilated by a lung simulator with entrained carbon dioxide (CO2) at respiratory rates (RR) of 15-45 min-1 and at 18 min-1 with chronic obstructive pulmonary disease (COPD) breathing patterns. Clearance was assessed at NHF of 20-60 L/min with a symmetrical interface (SI) and an asymmetrical interface (AI). CO2 kinetics visualized by infrared spectroscopy and mathematical modeling were used to study the mechanisms of clearance. At a higher RR (35 min-1) and NHF of 60 L/min, clearance in the upper airway was significantly higher with the AI when compared with the SI (29.64 ± 9.96%, P < 0.001), as opposed to at a lower RR (15 min-1) (1.40 ± 6.25%, P > 0.05), (means ± SD). With COPD breathing, clearance by NHF was reduced but significantly improved with the AI by 45.93% relative to the SI at NHF 20 L/min (P < 0.0001). The maximum pressure achieved with the AI was 6.6 cmH2O and NHF was 60 L/min at the end of expiration. Pressure differences between nasal cavities led to the reverse flow observed in the optical model. Asymmetrical NHF increases dead-space clearance by reverse flow through the choanae and accelerates purging of expired gas via the less occluded nare.NEW & NOTEWORTHY The asymmetrical interface generated reverse flow in the nasal cavities and across the choana, which led to unidirectional purging of expired gas from the upper airways. This accelerated the clearance of anatomical dead space and reduced re-breathing while increased resistance to flow resulted in higher positive end-expiratory pressure (PEEP). These findings are relevant to patients with elevated respiratory rates or with expiratory flow limitations where dead-space clearance by NHF can be substantially reduced.

Increased malignancies in our Waikato cohort of patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) has been associated with an increased risk of malignancy (especially in the skin, lung, breast, and hematological system). AIM: To determine the risk of malignancies in our SSc cohort. METHODS: The NZ National Cancer Registry supplied details of all malignancies recorded in patients attending the Waikato Hospital Systemic Sclerosis Clinics from 2005 to 2018. Prospectively gathered clinical data were used to look for associations between clinical variables and malignancy. RESULTS: Out of the 164 patients in the Waikato SSc cohort, 32 (19.5%) had developed a malignancy. The overall standardized incidence rate was found to be 2.2 (95% CI 1.4-3.4) but was higher for men (4.4, 95% CI 1.4-10.3). The absolute numbers of patients with SSc and malignancies were small and were not adequately powered to investigate the SSc subgroups. The mean age of patients with malignancy was approximately 8 years older than patients without. The most common form of malignancy was skin (14, 43.7%), followed by breast (6, 18.7%), and lymphoma (5, 15.6%). CONCLUSION: This study found an increased risk of malignancy for patients within the Waikato SSc cohort. Risk was greater in male patients and the mean age of patients with malignancies was approximately 8 years older than those without malignancy.

CCAAT/enhancer-binding proteins (C/EBP) beta and delta activate osteocalcin gene transcription and synergize with Runx2 at the C/EBP element to regulate bone-specific expression.

CCAAT/enhancer-binding proteins (C/EBP) are critical determinants for cellular differentiation and cell type-specific gene expression. Their functional roles in osteoblast development have not been determined. We addressed a key component of the mechanisms by which C/EBP factors regulate transcription of a tissue-specific gene during osteoblast differentiation. Expression of both C/EBPbeta and C/EBPdelta increases from the growth to maturation developmental stages and, like the bone-specific osteocalcin (OC) gene, is also stimulated 3-6-fold by vitamin D(3), a regulator of osteoblast differentiation. We characterized a C/EBP enhancer element in the proximal promoter of the rat osteocalcin gene, which resides in close proximity to a Runx2 (Cbfa1) element, essential for tissue-specific activation. We find that C/EBP and Runx2 factors interact together in a synergistic manner to enhance OC transcription (35-40-fold) in cell culture systems. We show by mutational analysis that this synergism is mediated through the C/EBP-responsive element in the OC promoter and by a direct interaction between Runx2 and C/EBPbeta. Furthermore, we have mapped a domain in Runx2 necessary for this interaction by immunoprecipitation. A Runx2 mutant lacking this interaction domain does not exhibit functional synergism. We conclude that, in addition to Runx2 DNA binding functions, Runx2 can also form a protein complex at C/EBP sites to regulate transcription. Taken together, our findings indicate that C/EBP is a principal transactivator of the OC gene and the synergism with Runx2 suggests that a combinatorial interaction of these factors is a principal mechanism for regulating tissue-specific expression during osteoblast differentiation.