The oxyhaemoglobin dissociation curve is generally left-shifted in COVID-19 patients at admission to hospital, and this is associated with lower mortality.

Lung damage caused by SARS-Cov-2 virus results in marked arterial hypoxia, accompanied in many cases by hypocapnia. The literature is inconclusive as to whether these conditions induce alteration of the affinity of haemoglobin for oxygen. We studied the oxyhaemoglobin dissociation curves (ODCs) of 517 patients hospitalized with coronavirus disease 2019 (COVID-19) for whom arterial blood gas analysis (BGA) was performed upon hospitalization (i.e., before treatment). With respect to a conventional normal p50 (pO2 at 50% saturation of haemoglobin) of 27 mmHg, 76% had a lower standardized p50 (p50s) and 85% a lower in vivo p50 (p50i). In a 33-patient subgroup with follow-up BGAs after 3, 6, 9, 12, 15 and 18 days' treatment, p50s and p50i exhibited statistically significant differences between baseline values and values recorded at all these time points. The 30-day Kaplan-Meier survival curves of COVID-19 patients stratified by p50i level show a higher probability of survival among patients who at admission had p50 values below 27 mmHg (p = 0.012). Whether the observed alteration of the affinity of haemoglobin for oxygen in COVID-19 patients is a direct or indirect effect of the virus on haemoglobin is unknown.

At-admission HbA1c levels in hospitalized COVID-19 participants with and without known diabetes.

BACKGROUND: To examine glycaemic status, and the impact of at-admission HbA1c levels on outcome, in a large group of participants hospitalized for COVID-19. METHODS: We inclued 515 participants with confirmed COVID-19 infection, with or without known diabetes, who met the following additional criteria: 1) age > 18 years, 2) HbA1c was determined at admission; 3) fasting plasma glucose was determined in the week of admission, and 4) discharge or death was reached before the end of the study. We examined attributes of participants at admission and 3-6 months post-discharge. To assess the associations of pre-admission attributes with in-hospital mortality, logistic regression analyses were performed. RESULTS: Mean age was 70 years, 98.8% were of white race, 49% were female, 31% had known diabetes (KD), an additional 7% met the HbA1c criterion for diabetes, and 13.6% died. In participants with KD, FPG and HbA1c levels were not associated with mortality in adjusted analyses; however, in participants without KD, whereas FPG showed direct association with mortality, HbA1c showed slight inverse association. CONCLUSIONS: There was a very high prevalence of people without KD with HbA1c levels above normal at-admission. This alteration does not seem to have been related to blood glucose levels.

Prediabetes defined by HbA1c and by fasting glucose: differences in risk factors and prevalence.

AIMS: To investigate, in a sample of nondiabetic adults from a Spanish community, the differences between prediabetes as defined by HbA1c ("H-prediabetes") and by fasting plasma glucose (FPG) ("F-prediabetes") in regard to prevalence and the influence of potential risk factors, adjusting the latter for confounders. METHODS: A total of 1328 nondiabetic participants aged ≥ 18 years were classified as normoglycemic, H-prediabetic [HbA1c 5.7-6.4% (39-47 mmol/mol)] or F-prediabetic (FPG 5.6-6.9 mmol/L). Multivariable analyses were used to compare the impacts of risk factors on the prevalence of H-prediabetes, F-prediabetes and their conjunctive and disjunctive combinations ("HaF-prediabetes" and "HoF-prediabetes," respectively). RESULTS: Some 29.9% of participants were HoF-prediabetic, 21.7% H-prediabetic, 16.3% F-prediabetic and only 8.1% HaF-prediabetic. Whatever the definition of prediabetes, increasing age, fasting insulin and LDL cholesterol were each a risk factor after adjustment for all other variables. Increasing BMI and decreasing mean corpuscular hemoglobin (MCH) were additional risk factors for H-prediabetes; male sex and increasing uric acid for F-prediabetes and increasing BMI for HaF-prediabetes. The participants satisfying the compound condition "hypertension or hyperlipidemia or obesity or hyperuricemia" (59.9% of the whole study group) included 83.1% of all subjects with HoF-prediabetes. CONCLUSIONS: In this population, the most sensitive risk factor for detection of prediabetes was age, followed by fasting insulin, LDL cholesterol, BMI, MCH, male sex and uric acid, with differences depending on the definition of prediabetes. MCH, an indirect measure of erythrocyte survival, significantly influences the prevalence of HbA1c-defined prediabetes. This study suggests that screening of individuals with selected risk factors may identify a high proportion of prediabetic persons.

Continuous glucose monitoring is more sensitive than HbA1c and fasting glucose in detecting dysglycaemia in a Spanish population without diabetes.

AIMS: To investigate whether continuous glucose monitoring (CGM) reveals patterns of glycaemic behaviour, the detection of which might improve early diagnosis of dysglycaemia. METHODS: A total 1521 complete days of valid CGM data were recorded under real-life conditions from a healthy sample of a Spanish community, as were matching FPG and HbA1C data. No participant was pregnant, had a history of kidney or liver disease, or was taking drugs known to affect glycaemia. RESULTS: CGM and fingerstick measurements showed a mean relative absolute difference of 6.9 ±â€¯2.2%. All subjects were normoglycaemic according to FPG and HbA1C except 21% who were prediabetic. The normoglycaemic subjects had a 24-hour mean blood glucose concentration (MBG) of 5.7 ±â€¯0.4 mmol/L, spending a median of 97% of their time within the target range (3.9-7.8 mmol/L). 73% of them experienced episodes with blood glucose levels above the threshold for impaired glucose tolerance, and 5% levels above the threshold for diabetes. These normoglycaemic participants with episodes of high glycaemia had glycaemic variabilities similar to those of prediabetic subjects with episodes of similar intensity or combined duration. CONCLUSIONS: CGM is a better indicator of possible early dysglycaemia than either FPG or HbA1c.

Impact of Mean Cell Hemoglobin on Hb A1c-Defined Glycemia Status.

BACKGROUND: Several hematological alterations are associated with altered hemoglobin A1c (Hb A1c). However, there have been no reports of their influence on the rates of exceeding standard Hb A1c thresholds by patients for whom Hb A1c determination is requested in clinical practice. METHODS: The initial data set included the first profiles (complete blood counts, Hb A1c, fasting glucose, and renal and hepatic parameters) of all adult patients for whom such a profile was requested between 2008 and 2013 inclusive. After appropriate exclusions, 21844 patients remained in the study. Linear and logistic regression models were adjusted for demographic, hematological, and biochemical variables excluded from the predictors. RESULTS: Mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) correlated negatively with Hb A1c. Fasting glucose, MCH, and age emerged as predictors of Hb A1c in a stepwise regression that discarded sex, hemoglobin, MCV, mean corpuscular hemoglobin concentration (MCHC), serum creatinine, and liver disease. Mean Hb A1c in MCH interdecile intervals fell from 6.8% (51 mmol/mol) in the lowest (≤27.5 pg) to 6.0% (43 mmol/mol) in the highest (>32.5 pg), with similar results for MCV. After adjustment for fasting glucose and other correlates of Hb A1c, a 1 pg increase in MCH reduced the odds of Hb A1c-defined dysglycemia, diabetes and poor glycemia control by 10%-14%. CONCLUSIONS: For at least 25% of patients, low or high MCH or MCV levels are associated with increased risk of an erroneous Hb A1c-based identification of glycemia status. Although causality has not been demonstrated, these parameters should be taken into account in interpreting Hb A1c levels in clinical practice.

Influence of the glycation gap on the diagnosis of type 2 diabetes.

AIMS: The results of using HbA1C-based criteria for diagnosis of type 2 diabetes and prediabetes have been reported to differ from those obtained using fasting plasma glucose (FPG) or an oral glucose tolerance test (OGTT). We aimed to determine whether these discrepancies might be due to the influence of the glycation gap. METHODS: For 430 patients without previously diagnosed diabetes for whom an OGTT had been requested in normal clinical practice, FPG, fructosamine and HbA1C were measured at the time of the test and again 1 month later. Glycaemia/diabetes status was classified as normoglycaemia, prediabetes or diabetes using both HbA1C-based and FPG/OGTT-based criteria, and their glycation gaps GG were calculated. RESULTS: The specificity of an HbA1C level of 6.5 % (48 mmol/mol) for diagnosis of FPG/OGTT-defined type 2 diabetes was 99 %, but its sensitivity was less than 37 %. HbA1C-diabetic patients had higher average blood glucose levels than FPG/OGTT-diabetic patients. With either set of criteria, high-GG patients were disproportionately numerous among those classified as diabetic and were disproportionately infrequent among those classified as normoglycaemic, but the effect was greater for the HbA1C criteria. CONCLUSIONS: The differences between HbA1C-based and FPG/OGTT-based diagnoses are largely due to the influence of the glycation gap, which may also influence the early stages of FPG/OGTT-defined diabetes.

Estimation of the glycation gap in diabetic patients with stable glycemic control.

OBJECTIVE: The glycation gap (the difference between measured A1C and the value predicted by regression on fructosamine) is stable and is associated with microvascular complications of diabetes but has not hitherto been estimated within a clinically useful time frame. We investigated whether two determinations 30 days apart suffice for a reasonably reliable estimate if both A1C and fructosamine exhibit stability. RESEARCH DESIGN AND METHODS: We studied 311 patients with type 1 or type 2 diabetes for whom simultaneous measurements of A1C and serum fructosamine had been made on at least two occasions separated by 1 month (t(0) and t(1)). Glycemia was deemed stable if A1C(t(1)) - A1C(t(0)) and fructosamine(t(1)) - fructosamine(t(0)) were both less than their reference change values (RCVs). Instantaneous glycation gaps [gg(t(0)) and gg(t(1))] and their mean (GG), were calculated using the data from all stable patients for the required regression. RESULTS: Stable glycemia was shown by 144 patients. In 90% of unstable case subjects, a change in medication was identified as the cause of instability. Among 129 stable patients with an average of eight gg determinations prior to t(0), GG correlated closely with the mean of these prior determinations (r(2) = 0.902, slope 1.025, intercept -0.038). CONCLUSIONS: The glycation gap can be calculated reliably from pairs of A1C and fructosamine measurements taken 1 month apart if these measurements satisfy the RCV criteria for glycemic control.

Progression of nephropathy in type 2 diabetes: the glycation gap is a significant predictor after adjustment for glycohemoglobin (Hb A1c).

BACKGROUND: The glycation gap has been proposed as an index of nonglycemic determinants of glycated hemoglobin (Hb A(1c)). We investigated whether it predicts progression of nephropathy in type 2 diabetic patients. METHODS: We recorded albumin excretion rate, Hb A(1c), and serum fructosamine in 2314 patients over an average of 6.5 years. Hb A(1c) was regressed on fructosamine by using a repeated-measures longitudinal regression model and data for all visits of all patients; the raw glycation gap gg was calculated at each visit, as measured by Hb A(1c) minus the value predicted by the regression; and the mean glycation gap (GG) was defined for each patient as the mean of the values for the raw glycation gap (gg) calculated at each visit. The study group was divided into high-, medium- and low-GG groups of equal sizes, which were compared for progression of nephropathy by Cox regression analyses controlling for age, sex, duration of diabetes, initial nephropathy status, therapy, baseline Hb A(1c), mean Hb A(1c), and mean fructosamine. The design of the study was a retrospective cohort study with follow-up for 6.5 (SD 4.2) years. RESULTS: The gg exhibited considerable stability over time. In the high- and medium-GG groups, the risk of progression of nephropathy was respectively 2.5 and 1.6 times that of the low-GG group (P < 0.0001 and P = 0.001, respectively) after adjustment as described above. CONCLUSIONS: GG predicts the progression of nephropathy in type 2 diabetic patients independently of fructosamine and even after adjustment for Hb A(1c). The joint use of the glycation gap and fructosamine as measures of nonglycemic and glycemic determinants of glycation, respectively, may improve evaluation of the risk of nephropathy and of the glycemic control desirable for the individual patient.

Tissue-polypeptide-specific antigen levels in diabetic patients with normal and pathological biochemical profiles.

OBJECTIVES: To identify causes for the raised TPS levels seen in diabetic patients. DESIGN AND METHODS: Relationships between TPS levels and biochemical markers for glycaemic control, hepatic dysfunction and renal dysfunction were investigated in 402 diabetic patients, none with evidence of cancer. RESULTS: Median TPS level (range) was 34.6 (19-276) U/L in controls versus 40.5 (16-691) U/L in type 1 diabetes mellitus (T1DM) patients and 53 (6-1654) U/L in type 2 diabetes mellitus (T2DM) patients. TPS levels above the 95th percentile were observed in 26.1% diabetic patients and in 68.6% of these diabetic patients, raised TPS was associated with clinical complications or biochemical indicators of hepatic and/or renal dysfunction. CONCLUSIONS: The raised mean TPS levels seen in diabetic patients appear to be mainly due to the existence of hepatic or renal dysfunction.

Treatment of mitochondrial encephalomyopathies with a xanthine oxidase inhibitor.

Five females with mitochondrial encephalomyopathies were treated for 3 to 7 years with a xanthine oxidase inhibitor (allopurinol, oral route, 20 mg/kg/day, in 2 or 3 doses daily). Clinical course was monitored in all patients. In addition, various metabolic variables, namely blood lactic acid, blood adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate were monitored, as well as energy charge. Data obtained were compared with data for an age-matched control group of 10 healthy children. Four of the five patients manifested clinical improvement, and the remaining patient exhibited slower disease progression. Three of the four patients who exhibited clinical improvement also had normalization of blood lactic acid level. All five patients had an increase in blood adenosine triphosphate levels and a decline in blood adenosine monophosphate; four of the five manifested a decline in blood adenosine diphosphate and increased energy charge. Mean blood adenosine triphosphate was significantly increased with respect to pretreatment levels and with respect to the control group; mean energy charge displayed an increase, though this was not statistically significant. In one patient, reduction of the allopurinol dose to 10 mg/kg/day was followed by a decline in both blood adenosine triphosphate level and energy charge, and by clinical worsening. In conclusion, the xanthine oxidase inhibitor allopurinol appears to have had beneficial effects in these patients in terms of both energy metabolism and clinical course.

Probing PrPSc structure using chemical cross-linking and mass spectrometry: evidence of the proximity of Gly90 amino termini in the PrP 27-30 aggregate.

Elucidation of the structure of PrP(Sc) continues to be one of the most important and difficult challenges in prion research. This task, essential for gaining an understanding of the basis of prion infectivity, has been hampered by the insoluble, aggregated nature of this molecule. We used a combination of chemical cross-linking, proteolytic digestion, and mass spectrometry (MALDI-TOF and nanoLC-ESI-QqTOF), in an attempt to gain structural information about PrP 27-30 purified from the brains of Syrian hamsters infected with scrapie. The rationale of this approach is to identify pairs of specific amino acid residues that are close enough to each other to react with a bifunctional reagent of a given chain length. We cross-linked PrP 27-30 with the amino-specific reagent bis(sulfosuccinimidyl) suberate (BS(3)), obtaining dimers, trimers, and higher-order oligomers that were separated by SDS-PAGE. In-gel digestion followed by mass spectrometric analysis showed that BS(3) reacted preferentially with Gly90. A cross-link involving two Gly90 amino termini was found in cross-linked PrP 27-30 dimers, but not in intramolecularly cross-linked monomers or control samples. This observation indicates the spatial proximity of Gly90 amino termini in PrP 27-30 fibrils. The Gly90-Gly90 cross-link is consistent with a recent model of PrP 27-30, based on electron crystallographic data, featuring a fiber composed of stacked trimers of PrP monomers; specifically, it is compatible with cross-linking of monomers stacked vertically along the fiber axis but not those adjacent to each other horizontally in the trimeric building block. Our results constitute the first measured distance constraint in PrP(Sc).

Neuron-specific enolase, nucleotides, nucleosides, purine bases, oxypurines and uric acid concentrations in cerebrospinal fluid of children with meningitis.

To determine the effects of meningitis on cerebral energy metabolism, cerebrospinal fluid concentrations of adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and urate were determined by high-performance liquid chromatography, and neuron-specific enolase by an enzyme immunoassay method, in 100 children with meningitis (45 bacterial, 46 viral and nine tuberculous), aged between 1 month and 13 years, and in 160 age-matched controls. Compared with controls, patients with bacterial meningitis showed high concentrations of hypoxanthine, xanthine and urate; patients with viral meningitis showed high concentrations of inosine, guanosine, xanthine, urate and neuron-specific enolase; and patients with tuberculous meningitis showed very high concentrations of inosine, xanthine and urate. Xanthine and urate concentrations were significantly higher in patients with tuberculous meningitis than in patients with viral or bacterial meningitis. These results suggest that in the acute stage of bacterial, viral and tuberculous meningitis, neuronal energy metabolism may be altered. The measurement of cerebrospinal xanthine and uric acid concentrations may be useful for the early diagnosis of a tuberculous origin.