The purpose of this study was to compare cardiovascular and respiratory effects of two volumes of bupivacaine 0.25% (0.2 mL kg-1-treatment BUP02-and 0.4 mL kg-1 -treatment BUP04) administered ...epidurally at the lumbosacral intervertebral space in dogs anesthetized with isoflurane. This experimental prospective randomized crossover design trial used six mixed breed adult dogs, four neutered males and two spayed females. Each dog was anesthetized on three different occasions: the first for isoflurane minimum alveolar concentration (MAC) measurement, and the following two assigned treatments (BUP02 or BUP04). On the two treatment days, anesthesia was induced and maintained with isoflurane at 1.3 MAC during the experiments. Cardiovascular and respiratory measurements were recorded before (T0) and 5, 15, 30, 60 and 90 minutes after the epidural administration of bupivacaine. Comparisons between and within groups were performed by a mixed-model ANOVA and Friedman's test when appropriate followed by Bonferroni post-hoc test or Dunnet's test to compare time points within each treatment with T0 (p < 0.05). Mean arterial pressure decreased significantly from 15 to 90 minutes after the administration of BUP02 and from 5 to 60 minutes in BUP04, with lower values in BUP04 than in BUP02 lasting up to 30 minutes after bupivacaine administration. No significant changes in cardiac output and systemic vascular resistance were observed in either treatment. Hypoventilation was only detected in BUP04. Hemoglobin concentration and arterial oxygen content decreased after both treatment of bupivacaine with no significant decrease in oxygen delivery. Two dogs in BUP04 developed Horner's syndrome. The epidural administration of 0.4 mL.kg-1 of bupivacaine to dogs in sternal recumbency anesthetized with isoflurane 1.3 MAC caused more cardiovascular and respiratory depression than 0.2 mL.kg-1.
Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe ...children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4‐year‐old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh‐like lesions on brain imaging. She died shortly after. Her 8‐year‐old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.
To assess the global effect of preterm birth on fetal metabolism and maternal–fetal nutrient transfer, we used a mass spectrometric-based chemical phenotyping approach on cord blood obtained at the ...time of birth. We sampled umbilical venous, umbilical arterial, and maternal blood from mothers delivering very-low birth weight (VLBW, with a median gestational age and weight of 29 weeks, and 1210 g, respectively) premature or full-term (FT) neonates. In VLBW group, we observed a significant elevation in the levels and maternal-fetal gradients of butyryl-, isovaleryl-, hexanoyl- and octanoyl-carnitines, suggesting enhanced short- and medium chain fatty acid β-oxidation in human preterm feto-placental unit. The significant decrease in glutamine-glutamate in preterm arterial cord blood beside lower levels of amino acid precursors of Krebs cycle suggest increased glutamine utilization in the fast growing tissues of preterm fetus with a deregulation in placental glutamate-glutamine shuttling. Enhanced glutathione utilization is likely to account for the decrease in precursor amino acids (serine, betaine, glutamate and methionine) in arterial cord blood. An increase in both the circulating levels and maternal–fetal gradients of several polyamines in their acetylated form (diacetylspermine and acetylputrescine) suggests an enhanced polyamine metabolic cycling in extreme prematurity. Our metabolomics study allowed the identification of alterations in fetal energy, antioxidant defense, and polyamines and purines flux as a signature of premature birth.
Betaine is an "alternate" methyl donor for homocysteine remethylation catalyzed by betaine homocysteine methyltransferase (BHMT), an enzyme mainly expressed in the liver and kidney. Betaine has been ...used for more than 30 years in pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) and cobalamin C (cblC) deficiencies to lower the hyperhomocysteinemia, although little is known about the optimal therapeutic dosage and its pharmacokinetic in these patients.
We compared 2 betaine doses (100 mg/kg/day vs. 250 mg/kg/day) in children affected by pnrCBS or cblC deficiencies. We also measured the pharmacokinetics parameters after a single dose of betaine (100 or 250 mg/kg) in these patients.
We conducted a prospective, randomized, crossover clinical trial with blinded evaluation. The primary outcome was the equivalence of total plasma homocysteine (tHcy) concentrations upon one-month oral treatment with betaine at 100 versus 250 mg/kg/day.
Eleven patients completed the study (5 pnrCBS and 6 cblC). tHcy concentrations were equivalent after a one-month treatment period for the two betaine dosages. Multivariate analysis showed a significant effect of betaine dose on methionine (Met) (p = 0.01) and S-adenosylmethionine (SAM) concentrations (p = 0.006).
Our analysis shows that there is no overt benefit to increasing betaine dosage higher than 100 mg/kg/day to lower tHcy concentrations in pnrCBS and cblC deficiencies. However, increasing betaine up to 250 mg/kg/d could benefit cblC patients through the increase of methionine and SAM concentrations, as low Met and SAM concentrations are involved in the pathophysiology of this disease. In contrast, in pnrCBS deficiency, betaine doses higher than 100 mg/kg/day could be harmful to these patients with pre-existing hypermethioninemia.
Clinical Trials, NCT02404337. Registered 23 May 2015-prospectively registered, https://clinicaltrials.gov .
Depletion of blood glutathione (GSH), a key antioxidant, is known to occur in preterm infants.
Our aim was to determine: 1) whether GSH depletion is present at the time of birth; and 2) whether it is ...associated with insufficient availability of cysteine (cys), the limiting GSH precursor, or a decreased capacity to synthesize GSH.
Sixteen mothers delivering very low birth weight infants (VLBW), and 16 mothers delivering healthy, full term neonates were enrolled. Immediately after birth, erythrocytes from umbilical vein, umbilical artery, and maternal blood were obtained to assess GSH GSH and cysteine cys concentrations, and the GSH synthesis rate was determined from the incorporation of labeled cysteine into GSH in isolated erythrocytes ex vivo, measured using gas chromatography mass spectrometry.
Compared with mothers delivering at full term, mothers delivering prematurely had markedly lower erythrocyte GSH and cys and these were significantly depressed in VLBW infants, compared with term neonates. A strong correlation was found between maternal and fetal GSH and cysteine levels. The capacity to synthesize GSH was as high in VLBW as in term infants.
The current data demonstrate that: 1) GSH depletion is present at the time of birth in VLBW infants; 2) As VLBW neonates possess a fully active capacity to synthesize glutathione, the depletion may arise from inadequate cysteine availability, potentially due to maternal depletion. Further studies would be needed to determine whether maternal-fetal cysteine transfer is decreased in preterm infants, and, if so, whether cysteine supplementation of mothers at risk of delivering prematurely would strengthen antioxidant defense in preterm neonates.
Abstract Introduction Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1 , resulting in impaired glucose uptake through the ...blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia). The aim of our study was to provide a comprehensive overview of GLUT1DS in a French cohort. Methods 265 patients were referred to the French national laboratory for molecular screening between July 2006 and January 2012. Mutations in SLC2A1 were detected in 58 patients, with detailed clinical data available in 24, including clinical features with a focus on their epileptic pattern and electroencephalographic findings, biochemical findings and neuroimaging findings. Results 53 point mutations and 5 deletions in SLC2A1 were identified. Most patients (87.5%) exhibited classic phenotype with intellectual deficiency (41.7%), epilepsy (75%) or movement disorder (29%) as initial symptoms at a medium age of 7.5 months, but diagnostic was delayed in most cases (median age at diagnostic 8 years 5 months). Sensitivity to fasting or exertion in combination with those 3 main symptoms were the main differences between mutated and negative patients (p < 0.001). Patients with myoclonic seizures (52%) evolved with more severe intellectual deficiency and movement disorders compared with those with Early Onset Absence Epilepsy (38%). Three patients evolved from a classic phenotype during early childhood to a movement disorder predominant phenotype at a late childhood/adulthood. Conclusions Our data confirm that the classic phenotype is the most frequent in GLUT1DS. Myoclonic seizures are a distinctive feature of severe forms. However a great variability among patients and overlapping through life from milder classic phenotype to paroxysmal-prominent- movement-disorder phenotype are possible, thus making it difficult to identify definite genotype–phenotype correlations.
Preterm birth is associated with higher risks of suboptimal neurodevelopment and cardiometabolic disease later in life. Altered maternal-fetal lipid supply could play a role in such risks. Our ...hypothesis was that very preterm infants born with very low birth weight (VLBW) have altered lipidome and apolipoprotein profiles, compared with term infants.
Seven mothers of VLBW infants born at <32 GA and 8 full-term mother-infant dyads were included. Cholesterol and triglycerides in lipoproteins were determined in maternal plasma and in the two blood vessels of the umbilical cord (vein (UV) and artery (UA)) following FPLC isolation. Apolipoprotein concentrations in lipoproteins and plasma lipidomic analysis were performed by LC-MS/MS.
We found higher cholesterol and VLDL-cholesterol in UV and UA and lower apolipoprotein A-I in HDL2 in UV in preterm neonates. Phosphatidylcholine (PC) containing saturated and monounsaturated fatty acids and specific sphingomyelin species were increased in UV and UA, whereas PC containing docosahexaenoic acid (DHA) was reduced in UV of VLBW neonates.
Lower DHA-PC suggests a lower DHA bioavailability and may contribute to the impaired neurodevelopment. Altered HDL-2, VLDL, and sphingomyelin profile reflect an atherogenic risk and increased metabolic risk at adulthood in infants born prematurely.
Lower ApoA-I in HDL2, and increased specific sphingomyelin and phosphatidylcholine containing saturated and monounsaturated fatty acid could explain the accumulation of cholesterol in umbilical vein in VLBW preterm neonates. Decreased phosphatidylcholine containing DHA suggest a reduced DHA availability for brain development in VLBW preterm infants. Characterization of alterations in fetal lipid plasma and lipoprotein profiles may help to explain at least in part the causes of the elevated cardiovascular risk known in people born prematurely and may suggest that a targeted nutritional strategy based on the composition of fatty acids carried by phosphatidylcholine may be promising in infants born very early.
A Cause of Permanent Ketosis: GLUT-1 Deficiency Chenouard, Alexis; Vuillaumier-Barrot, Sandrine; Seta, Nathalie ...
JIMD Reports, Volume 18,
01/2015, Letnik:
18
Book Chapter, Journal Article
Recenzirano
Odprti dostop
GLUT-1-deficiency syndrome (GLUT1-DS; OMIM 606777) is a treatable metabolic disorder caused by a mutation of SLC2A1 gene. The functional deficiency of the GLUT1 protein leads to an impaired glucose ...transport into the brain, resulting in neurologic disorders.
We report on a 6-month-old boy with preprandial malaises who was treated monthly by a sorcerer because of a permanent acetonemic odor. He subsequently developed pharmaco-resistant seizures with microcephaly and motor abnormalities. Metabolic explorations were unremarkable except for a fasting glucose test which revealed an abnormal increase of blood ketone bodies. At the age of 35 months, GLUT1-DS was diagnosed based on hypoglycorrhachia with a decreased CSF to blood glucose ratio, and subsequent direct sequencing of the SLC2A1 gene revealed a de novo heterozygous mutation, c.349A>T (p.Lys117X) on exon 4. It was noteworthy that the patient adapted to the deficient cerebral glucose transport by permanent ketone body production since early life. Excessive ketone body production in this patient provided an alternative energy substrate for his brain. We suggest a cerebral metabolic adaptation with upregulation of monocarboxylic acid transporter proteins (MCT1) at the blood–brain barrier provoked by neuroglycopenia and allowing ketone body utilization by the brain. This case illustrates that GLUT1-DS should be considered in the differential diagnosis of permanent ketosis.
Purpose
We compared respiratory mechanics between the positive end-expiratory pressure of minimal respiratory system elastance (PEEP
minErs
) and three levels of PEEP during low-tidal-volume ...(6 mL/kg) ventilation in rats.
Methods
Twenty-four rats were anesthetized, paralyzed, and mechanically ventilated. Airway pressure (
P
aw
), flow (
F
), and volume (
V
) were fitted by a linear single compartment model (LSCM)
P
aw
(
t
) =
E
rs
×
V
(
t
) +
R
rs
×
F
(
t
) + PEEP or a volume- and flow-dependent SCM (VFDSCM)
P
aw
(
t
) = (
E
1
+
E
2
×
V
(
t
)) ×
V
(
t
) + (
K
1
+
K
2
× |
F
(
t
)|) ×
F
(
t
) + PEEP, where
E
rs
and
R
rs
are respiratory system elastance and resistance, respectively;
E
1
and
E
2
×
V
are volume-independent and volume-dependent
E
rs
, respectively; and K
1
and K
2
×
F
are flow-independent and flow-dependent
R
rs
, respectively. Animals were ventilated for 1 h at PEEP 0 cmH
2
O (ZEEP); PEEP
minErs
; 2 cmH
2
O above PEEP
minErs
(PEEP
minErs+2
); or 4 cmH
2
O above PEEP
minErs
(PEEP
minErs+4
). Alveolar tidal recruitment/derecruitment and overdistension were assessed by the index %
E
2
= 100 × (
E
2
×
V
T
)/(
E
1
+ |
E
2
| ×
V
T
), and alveolar stability by the slope of
E
rs
(
t
).
Results
%
E
2
varied between 0 and 30% at PEEP
minErs
in most respiratory cycles. Alveolar Tidal recruitment/derecruitment (%
E
2
< 0) and overdistension (%
E
2
> 30) were predominant in the absence of PEEP and in PEEP levels higher than PEEP
minErs
, respectively. The slope of
E
rs
(t) was different from zero in all groups besides PEEP
minErs+4
.
Conclusions
PEEP
minErs
presented the best compromise between alveolar tidal recruitment/derecruitment and overdistension, during 1 h of low-
V
T
mechanical ventilation.
: Zinc is a cofactor for several enzymes involved in many metabolisms. Zinc deficiency induces various disorders such as acrodermatitis enteropathica, either inherited or acquired. We report three ...cases of premature infants (24–31 wks gestational age) with low birthweight (650 to 940 g) and enteropathy, two of whom presented with necrotizing enterocolitis. All infants were fed by total parenteral nutrition. At a chronological age ranging from 73 to 80 days, all infants developed a periorificial dermatitis. Before the onset of the first signs, they had received zinc supplementation ranging from 146% to 195% of the recommended dose (400 μg/kg/day). Increased zinc supplementation over a course of 6–18 days induced a complete resolution of symptoms in all cases. No abnormality in the neurologic examination and no recurrence were observed at the end of the zinc treatment. Low birthweight premature infants with enteropathy on total parenteral nutrition are at risk of developing zinc deficiency. The usual recommended zinc supplementation is probably insufficient for those infants. A delay in the diagnosis of zinc deficiency may lead to severe complications.
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