Hypoalbuminemia in COVID-19: assessing the hypothesis for underlying pulmonary capillary leakage.

BACKGROUND: Since the first observations of patients with COVID-19, significant hypoalbuminaemia was detected. Its causes have not been investigated yet. OBJECTIVE: We hypothesized that pulmonary capillary leakage affects the severity of respiratory failure, causing a shift of fluids and proteins through the epithelial-endothelial barrier. METHODS: One hundred seventy-four COVID-19 patients with respiratory symptoms, 92 admitted to the intermediate medicine ward (IMW) and 82 to the intensive care unit (ICU) at Luigi Sacco Hospital in Milan, were studied. RESULTS: Baseline characteristics at admission were considered. Proteins, interleukin 8 (IL-8) and interleukin 10 (IL-10) in bronchoalveolar lavage fluid (BALF) were analysed in 26 ICU patients. In addition, ten autopsy ultrastructural lung studies were performed in patients with COVID-19 and compared with postmortem findings in a control group (bacterial pneumonia-ARDS and H1N1-ARDS). ICU patients had lower serum albumin than IMW patients [20 (18-23) vs 28 (24-33) g L-1 , P < 0.001]. Serum albumin was lower in more compromised groups (lower PaO2 -to-FiO2 ratio and worst chest X-ray findings) and was associated with 30 days of probability of survival. Protein concentration was correlated with IL-8 and IL-10 levels in BALF. Electron microscopy examinations of eight out of ten COVID-19 lung tissues showed loosening of junctional complexes, quantitatively more pronounced than in controls, and direct viral infection of type 2 pneumocytes and endothelial cells. CONCLUSION: Hypoalbuminaemia may serve as severity marker of epithelial-endothelial damage in patients with COVID-19. There are clues that pulmonary capillary leak syndrome plays a key role in the pathogenesis of COVID-19 and might be a potential therapeutic target.

[Analysis of corneal and conjunctival sensitivities and its related factors of premature babies].

Objective: To analyse the corneal and conjunctival sensitivities of premature babies and to study the relevant influencing factors. Methods: Cross-sectional study. One hundred premature infants born at Women's Hospital School of Medicine Zhejiang University between May 2015 and September 2015 were enrolled, among which 51 were male (51%) and 49 were female (49%), the mean gestational age was (30.93±1.75)w, the mean corrected gestational age was (33.65±1.53)w, the mean birth weight was (1 592±336)g. The thresholds of cornea and conjunctiva of infants' left or right eyes were measured with Cochet-Bonnet aesthesiometer at 8-10 o'clock every morning when they naturally woke up, the minimum length of nylon wire that induced three successive times of eye-blink responses was recorded. Paired sample t test was used to compare the corneal and conjunctival sensitivities, the ocular surface sensitivities of preterm infants of different gender were compared using independent samples t-test, Pearson correlation and multiple linear regression analysis was conducted to analyze the correlation of corneal and conjuncitval sensitivities with gestational age, birth weight, age and corrected gestational age. Results: The mean corneal sensitivity was (44.85±5.53) mm and the mean conjunctival sensitivity was (23.50±5.48)mm in premature babies, corneal sensitivity was significantly higher than conjunctival sensitivity (t=25.620, P<0.001). No statistical significance was found between male and female preterm infants in corneal sensitivity [(44.80±5.83) mm vs. (44.90±5.25) mm, t=-0.085, P=0.933] and conjunctival sensitivity[(23.14±5.83) mm vs. (23.88±5.13) mm, t=-0.673, P=0.502]. Pearson correlation analysis showed that corneal sensitivity was significantly associated with conjunctival sensitivity in prematurity(r=0.676, P<0.001). There was significant correlation between corneal sensitivity and age, corrected gestational age (r=0.238, P=0.017; r=0.679, P<0.001), however no significant correlation was found between corneal sensitivity and gestational age, birth weight in preterm infants (r=0.067, P=0.510; r=-0.179, P=0.075). There was significant correlation between conjunctival sensitivity and corrected gestational age (r=0.490, P<0.001), however no significant correlation was found between conjunctival sensitivity and gestational age, birth weight and age in preterm infants (r=0.078, P=0.439; r=-0.096, P=0.344; r=0.151, P=0.133). Multiple linear regression revealed that corneal sensitivity(Y1) was positively correlated with corrected gestational age(X), the regression equation was Y1=2.45X-37.52, the conjunctical sensitivity(Y2) was also positively correlated with corrected gestational age(X), the regression equation was Y2=1.75X-35.41. Conclusions: The corneal sensitivity is higher than conjunctival sensitivity in premature babies.No statistical significance is found between male and female preterm infants in corneal sensitivity and conjunctival sensitivity. The corneal sensitivity and conjunctival sensitivity are correlated with corrected gestational age in preterm infants. The corneal and conjunctival sensitivities of premature babies tend to increase along with the increase of corrected gestational age. (Chin J Ophthalmol, 2018, 54: 115-119).

Efficacy of on-demand treatment in reducing morbidity in patients with hereditary angioedema due to C1 inhibitor deficiency.

BACKGROUND: Angioedema due to hereditary deficiency of C1 inhibitor causes temporarily disability. Guidelines recommend early on-demand treatment of attacks to reduce morbidity. In this prospective observational study, we evaluated the efficacy of on-demand approach. METHODS: From January 2009 to August 2014, data on attacks and treatments were collected from 227 patients from our centre in Milan. RESULTS: A total of 4244 attacks were reported; 50% were treated with approved therapies (pdC1-INH or icatibant), 15% were with tranexamic acid, and 35% were not treated. Attack locations were peripheral cutaneous (46%), abdominal (34%), multiple (12%), facial (5%) and laryngeal (3%). Attack severities were moderate (48%), mild (28%) and severe (24%). Median attack duration (data available for 2393 attacks) with approved therapies was 10 h, significantly shorter than without treatment (45 h) or with tranexamic acid (38 h). Most of the treatments were self-administered: 93% with icatibant and 59% with pd-C1-INH. Median attack duration with icatibant was 8 and 11.5 h with pd-C1 INH. Median time from onset of symptoms to drug administration was 1 h with icatibant and 2 h with pd-C1INH and median time from drug administration to complete resolution was 5.5 and 8 h, respectively. Second treatment was required in 12.7% of icatibant-treated attacks and in 1.9% of pdC1-INH-treated attacks. CONCLUSION: This study provides evidence that on-demand treatment is effective in reducing disease-related morbidity. The use of on-demand treatment in Italy has increased up to 50% of attacks in the last years, reflecting a better adherence to international guidelines.

Presentation, diagnosis and treatment of angioedema without wheals: a retrospective analysis of a cohort of 1058 patients.

BACKGROUND: The first classification of angioedema without wheals was recently reported and comprises different forms of the disease distinguished by aetiology, mediator of oedema and inheritance. METHODS: In total, 1725 consecutive patients with angioedema without wheals were examined at our centre between 1993 and 2012. We excluded from the analysis 667 patients because of incomplete data or because angioedema was related to a specific factor. RESULTS: According to the new classification of angioedema, the 1058 patients included in this analysis were diagnosed with hereditary (HAE; n = 377) or acquired angioedema (AAE; n = 681). The former group included HAE with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE; n = 353) and HAE with normal C1-INH levels (n = 24), of which six had a factor XII mutation (FXII-HAE) and 18 had disease of unknown origin (U-HAE). The AAE group included disease with C1-INH deficiency (C1-INH-AAE; n = 49), AAE related to angiotensin-converting enzyme inhibitor treatment (n = 183), idiopathic histaminergic (IH-AAE; n = 379) and idiopathic nonhistaminergic angioedema (InH-AAE; n = 70). We compared hereditary and AAE with uncertain aetiopathogenesis: the FXII-HAE and U-HAE groups pooled (FXII/U-HAE) versus InH-AAE. The median age at onset of FXII/U-HAE and InH-AAE was 26 and 38 years, respectively. In addition, 56% of patients with FXII/U-HAE and 81% of those with InH-AAE reported more than five attacks per year (median duration of 48 h). The location of angioedema in patients with FXII/U-HAE versus those with InH-AAE was the following: face, 70% versus 86%; tongue, oral cavity or larynx, 55% versus 68%; limbs, 70% versus 56%; and gastrointestinal mucosa, 50% versus 20%. Prophylaxis with tranexamic acid was effective in all six patients with U-HAE and in 37 of 38 with InH-AAE who were started on this treatment. CONCLUSION: Our findings in this cohort of patients with angioedema provide new information on the clinical characteristics, diagnosis and treatment of this disease.

Assembly of the mitochondrial membrane system. Analysis of structural mutants of the yeast coenzyme QH2-cytochrome c reductase complex.

Coenzyme QH2-cytochrome c reductase is a multisubunit complex of the mitochondrial respiratory chain. Mutants of Saccharomyces cerevisiae with lesions in cytochromes b, c1, the non-heme iron protein, and the noncatalytic subunits have been used to study several aspects of the assembly of the complex. Strains with mutations in single subunits exhibit a variety of different phenotypes. Mutants in the 17-kDa (core 3) subunit grow normally on a nonfermentable substrate indicating that this component is not essential for either enzymatic activity or assembly of the enzyme. Mutations in all the other subunits express a respiratory-deficient phenotype and the absence of detectable enzyme activity. Among the respiratory-defective strains, some have mature cytochrome b (non-heme iron protein and cytochrome c1 mutants), while other mutants lack spectrally detectable cytochrome b and have reduced levels of the apoprotein (mutants in the 44-, 40-, 14-, and 11-kDa core subunits). Mutations in single subunits exert different effects on the concentrations of their partner proteins. These may be summarized as follows: 1) No substantial loss in the 44- or 40-kDa core subunits is seen in single mutants; 2) the concentration of cytochrome c1 is also relatively unaffected by mutations in the other subunits except for the cytochrome b mutant which has 60% of the wild type level of cytochrome c1; 3) all the single mutants have only 15-20% of the normal amount of non-heme iron protein; 4) mutations in the non-heme iron protein have no appreciable effect on the concentrations of the other subunits; 5) mutations in single subunits cause parallel decreases in the concentrations of cytochrome b, the 14-, and the 11-kDa subunits. These results indicate that the synthesis or stability of a subset of subunits depends on the presence of other subunit polypeptides of the complex. At present we favor the idea that the observed changes in the concentrations of some subunits are due to higher turnover rates of the proteins in a partially assembled complex. Based on the mutant phenotypes, a tentative model for the assembly of coenzyme QH2-cytochrome c reductase is proposed. According to this model it is envisioned that the subunits interact with one another in the lipid bilayer. Maturation of apocytochrome b occurs after it is assembled with the nonstructural subunits to form a core structure. This intermediate complex interacts with the non-heme iron protein to form the active holoenzyme.

Assembly of the mitochondrial membrane system. Characterization of COR1, the structural gene for the 44-kilodalton core protein of yeast coenzyme QH2-cytochrome c reductase.

The respiratory deficiency of yeast strains previously assigned to complementation group G7 has been ascribed to the absence in the mutants of functional cytochrome b. Since G7 mutants are capable of synthesizing the apoprotein, the primary effect of the mutations is to prevent maturation of this electron carrier. The recombinant plasmid pG7/T1 with a 6.7-kilobase pairs (kb) insert of wild type yeast nuclear DNA has been selected from a genomic library by transformation of a G7 mutant to respiratory competency. The genetically active region of the pG7/T1 insert has been subcloned on a 3-kb fragment of DNA which has been shown to contain an open reading frame encoding a protein of 50,236 Mr. In situ disruption of the reading frame causes a deficiency in cytochrome b. The strain with the disrupted gene fails to complement G7 mutants thereby confirming the correct identification of the gene henceforth referred to as COR1. The carboxyl-terminal half of the COR1 gene has been fused to the amino-terminal half of the Escherichia coli trpE gene in the high expression vector pATH2. This plasmid construct promotes a high level of expression of the trpE/COR1 hybrid protein. Antibodies against the purified hybrid protein react with a 44 kDa protein subunit of yeast coenzyme QH2-cytochrome c reductase corresponding to the largest core subunit of the complex. These data indicate that the yeast nuclear gene COR1 codes for the 44-kDa core protein and that the latter is required for the conversion of apocytochrome b to mature cytochrome b.