Cerebral blood flow responses to transient blood pressure challenges are frequently attributed to cerebral autoregulation (CA), yet accumulating evidence indicates vascular properties like compliance ...are also influential. We hypothesized that middle cerebral blood velocity (MCAv) dynamics during or following a transient blood pressure perturbation can be accurately explained by the windkessel mechanism. Eighteen volunteers underwent blood pressure manipulations, including bilateral thigh-cuff deflation and sit-to-stand maneuvers under normocapnic and hypercapnic (5% CO2) conditions. Pressure-flow recordings were analyzed using a windkessel analysis approach that partitions the frequency-dependent resistance and compliance contributions to MCAv dynamics. The windkessel was typically able to explain more than 50% of the MCAv variance, as indicated by R(2) values for both the flow recovery and postrecovery phase. The most consistent predictors of MCAv dynamics under the control condition were the windkessel capacitive gain and high-frequency resistive gain. However, there were significant interindividual variations in the composition of windkessel predictors. Hypercapnia consistently reduced the capacitive gain and enhanced the low-frequency (0.04-0.20 Hz) resistive gain for both thigh-cuff deflation and sit-to-stand trials. These findings indicate that 1) MCAv dynamics during acute transient hypotension challenges are dominated by cerebrovascular windkessel properties independent of CA; 2) there is significant heterogeneity in windkessel properties between individuals; and 3) hemodynamic effects of hypercapnia during transient blood pressure challenges primarily reflect changes in windkessel properties rather than pure CA impairment.
•101 patients with HER2+ MBC on pertuzumab and trastuzumab were included.•Most observed cardiotoxicity were mild, all occurred early within 24 months.•Presence of cardiovascular co-morbidities ...predicts treatment cardiotoxicity.•Risk-stratified de-escalation of long-term cardiac surveillance should be discussed.
A variety of felsic and mafic granulites and ultramafic rocks occur as xenoliths within a 12.7 Ma ultrapotassic dyke intruding Xigaze flysch immediately to the north of the Yarlung-Tsangpo suture ...zone in southern Tibet. Garnet-clinopyroxene-plagioclase-quartz thermobarometry on mafic granulite xenoliths gives temperatures of 1130-1330°C and pressures between 22 and 26 kbar indicating equilibration in the high-pressure and ultrahigh-temperature granulite field and defining a geotherm of c. 16°C km-1. Ultramafic xenoliths consist mainly of hornblende and biotite, probably of restitic crustal rather than mantle origin, and attained peak metamorphic conditions of 920-1130°C and 17-24 kbar, whereas felsic granulites equilibrated at 870-900°C at an inferred pressure of 17 kbar. In situ U-(Th)-Pb laser ablation inductively coupled plasma mass spectrometry dating of zircons shows that protoliths may include Proterozoic basement rocks, Late Cretaceous calc-alkaline tonalites of the Gangdese batholith root and/or remnants of a Neo-Tethyan oceanic arc. Certain zircons from a felsic granulite and an ultramafic xenolith have mean 206Pb/238U ages of 16.8±0.9 Ma and 15.6±0.6 Ma, respectively, and monazites from a micaceous xenolith yielded a mean 208Pb/232Th age of 14.4±0.4 Ma. These results show that the southern Tibet basement reached a thickness of c. 80 km by 17-14 Ma at the latest and has remained unchanged until the present day.
Branched five carbon (C5) alcohols are attractive targets for microbial production due to their desirable fuel properties and importance as platform chemicals. In this study, we engineered a ...heterologous isoprenoid pathway in E. coli for the high-yield production of 3-methyl-3-buten-1-ol, 3-methyl-2-buten-1-ol, and 3-methyl-1-butanol, three C5 alcohols that serve as potential biofuels. We first constructed a pathway for 3-methyl-3-buten-1-ol, where metabolite profiling identified NudB, a promiscuous phosphatase, as a likely pathway bottleneck. We achieved a 60% increase in the yield of 3-methyl-3-buten-1-ol by engineering the Shine-Dalgarno sequence of nudB, which increased protein levels by 9-fold and reduced isopentenyl diphosphate (IPP) accumulation by 4-fold. To further optimize the pathway, we adjusted mevalonate kinase (MK) expression and investigated MK enzymes from alternative microbes such as Methanosarcina mazei. Next, we expressed a fusion protein of IPP isomerase and the phosphatase (Idi1~NudB) along with a reductase (NemA) to diversify production to 3-methyl-2-buten-1-ol and 3-methyl-1-butanol. Finally, we used an oleyl alcohol overlay to improve alcohol recovery, achieving final titers of 2.23 g/L of 3-methyl-3-buten-1-ol (~70% of pathway-dependent theoretical yield), 150 mg/L of 3-methyl-2-buten-1-ol, and 300 mg/L of 3-methyl-1-butanol.
The ethical concerns of refusing lifesaving treatments after receiving an already limited resource such as a solid organ transplantation in a Jehovah’s Witness patient have been discussed in the ...literature. Many of these studies have concluded that with a multidisciplinary approach, solid organ transplantation is possible in the setting of Jehovah’s Witness patients. To date, there are no reported cases of bilateral sequential lung transplantation in the literature. We report two successful cases of bilateral sequential lung transplantation in Jehovah’s Witness patients with excellent long-term follow-up.
Diabetes mellitus is the most common co-morbidity associated with necrotising fasciitis. This study aims to compare the clinical presentation, investigations, Laboratory Risk Indicator for ...Necrotising Fasciitis (LRINEC) score, microbiology and outcome of management of this condition in diabetic and non-diabetic patients.
The medical records of all patients with surgically proven necrotising fasciitis treated at our institution between 2005 and 2014 were reviewed. Diagnosis of necrotising fasciitis was made on findings of 'dishwater' fluid, presence of greyish necrotic deep fascia and lack of bleeding on muscle dissection found intra-operatively. Information on patients' demographics, presenting symptoms, clinical signs, investigations, treatment and outcome were recorded and analysed.
A total of 127 patients with surgically proven necrotising fasciitis were included in this study. In all, 78 (61.4%) were diabetic and 49 (38.6%) were non-diabetic. Diabetics tended to have polymicrobial infections (p = 0.03), renal impairment (p < 0.001), end-stage renal disease (p = 0.001) and multiple co-morbidities (p < 0.001). They presented atypically, with less tenderness (p = 0.042) and less hypotension (p = 0.034). This resulted in higher rates of misdiagnosis (p = 0.038) and a longer time to surgery (p = 0.05) leading to longer hospital stays (p = 0.043) and higher rates of amputation (p = 0.045). However, the rate of mortality is comparable (p = 0.525). A LRINEC score of > 8 appears to be more sensitive in diabetic patients (p < 0.001). However, the increased sensitivity in diabetic patients may be related to hyperglycemia and electrolyte abnormalities associated with renal impairment in these patients.
The LRINEC score must be used with caution in diagnosing necrotising fasciitis in diabetic patients. A high index of suspicion is key to the early diagnosis and subsequent management of these patients. Cite this article: Bone Joint J 2016;98-B:1563-8.
Abstract Objectives Accurate cancer localization and negative resection margins are necessary for successful segmentectomy. In this study, we evaluate a newly developed software package that permits ...automated segmentation of the pulmonary parenchyma, allowing 3-dimensional assessment of tumor size, location, and estimates of surgical margins. Methods A pilot study using a newly developed 3-dimensional computed tomography analytic software package was performed to retrospectively evaluate preoperative computed tomography images of patients who underwent segmentectomy (n = 36) or lobectomy (n = 15) for stage 1 non–small cell lung cancer. The software accomplishes an automated reconstruction of anatomic pulmonary segments of the lung based on bronchial arborization. Estimates of anticipated surgical margins and pulmonary segmental volume were made on the basis of 3-dimensional reconstruction. Results Autosegmentation was achieved in 72.7% (32/44) of preoperative computed tomography images with slice thicknesses of 3 mm or less. Reasons for segmentation failure included local severe emphysema or pneumonitis, and lower computed tomography resolution. Tumor segmental localization was achieved in all autosegmented studies. The 3-dimensional computed tomography analysis provided a positive predictive value of 87% in predicting a marginal clearance greater than 1 cm and a 75% positive predictive value in predicting a margin to tumor diameter ratio greater than 1 in relation to the surgical pathology assessment. Conclusions This preoperative 3-dimensional computed tomography analysis of segmental anatomy can confirm the tumor location within an anatomic segment and aid in predicting surgical margins. This 3-dimensional computed tomography information may assist in the preoperative assessment regarding the suitability of segmentectomy for peripheral lung cancers.
Blood stream infection (BSI) and acute GVHD (aGVHD) are serious complications of hematopoietic SCT (HSCT). We hypothesized that the two events were not independent of one another. We studied (1) ...associations between BSI and aGVHD; and (2) the impact of BSI and/or aGVHD on death within 100 days after HSCT, using a retrospective cohort analysis. Risk factor analysis was carried out using multivariable Cox proportional hazards analyses. Of 211 patients who underwent allogeneic HSCT from January 2000 to December 2005 (58% of whom underwent reduced intensity transplantation), 82 (39%) developed BSI. In 49 patients (23%), grade (gr) 2-4 aGVHD occurred. Early BSI was independently associated with an increased occurrence of subsequent aGVHD gr 2-4. CMV seropositivity was independently associated with decreased occurrence of aGVHD. aGVHD gr 2-4 independently predicted subsequent first BSI. Both BSI and aGVHD gr 2-4 were significant independent predictors of death within 100 days after HSCT. There is a strong, independent association between BSI and aGVHD. Potential explanations include the elaboration of cytokines during BSI favoring the development of aGVHD and/or the immunosuppressive treatment of aGVHD favoring the development of BSI. Future studies should be directed at the mechanistic investigations of this association.
Bacillus anthracis , the causative agent of anthrax, replicates as chains of vegetative cells by regulating the separation of septal peptidoglycan. Surface (S)-layer proteins and associated proteins ...(BSLs) function as chain length determinants and bind to the secondary cell wall polysaccharide (SCWP). In this study, we identified the B. anthracis lcpD mutant, which displays increased chain length and S-layer assembly defects due to diminished SCWP attachment to peptidoglycan. In contrast, the B. anthracis lcpB3 variant displayed reduced cell size and chain length, which could be attributed to increased deposition of BSLs. In other bacteria, LytR-CpsA-Psr (LCP) proteins attach wall teichoic acid (WTA) and polysaccharide capsule to peptidoglycan. B. anthracis does not synthesize these polymers, yet its genome encodes six LCP homologues, which, when expressed in S. aureus , promote WTA attachment. We propose a model whereby B. anthracis LCPs promote attachment of SCWP precursors to discrete locations in the peptidoglycan, enabling BSL assembly and regulated separation of septal peptidoglycan.
•Smoking, diabetes and obesity are not associated with increased postoperative infection in tibial plateau fractures.•Excessive alcohol consumption >13 units/week is the only independent predictor of ...infection after fixation of tibial plateau fractures.•Extra attention should be paid to perioperative antibiotics and postoperative surveillance for infection in such patients.
Surgical fixation of tibial plateau fractures has been shown to improve long-term functional outcomes, but a major complication is that of postoperative infection which can be deleterious to long-term outcomes. This study aims to assess the impact of common comorbidities on the risk of postoperative infection.
A retrospective study of 210 consecutive operatively treated patients, treated at two Level 1 Trauma Centres over a 27-month period was performed. Records were analysed to assess the presence of the study factors; smoking, alcohol intake >13 units/week, diabetes, and BMI > 30. The impact of these factors on infection was assessed with univariate and multivariate analyses.
175 patients were included in the study, 56.6% male with a mean age of 46.9 years (± 18.2 years). Excessive alcohol consumption of >13 units/week was the only significant risk factor for postoperative infection (p = 0.05) on multivariate analysis.
This study has identified excessive alcohol consumption as the only independent risk factor for postoperative infection in patients with all types of tibial plateau fracture treated with operative fixation. No relationship between smoking, diabetes nor obesity was found for postoperative infection.
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