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PubMed1984

Lidocaine therapy in awake endotoxemic Yucatan minipigs. I. Metabolic parameters and glucose biokinetics.

Cellular membrane destabilization induced by endotoxin and endogenous inflammatory mediators contributes significantly to the progression of metabolic and hemodynamic dysfunction in endotoxemia. Owing to its membrane-stabilizing properties, lidocaine may prove beneficial in the treatment of endotoxic shock. Twelve 50-kg pigs were surgically fitted with jugular venous and carotid arterial catheters. Seventy-two hours later they were placed in restraint slings, and following a 3-h control period, were infused with Escherichia coli endotoxin (Difco 055:B5) at 15 micrograms/kg for 6 h. Eight were controls and four received a primed (2 mg/kg) continuous infusion (2 mg/kg/h) of lidocaine 1 h following the initiation of endotoxin infusion. In the lidocaine-treated group, arterial hypotension (113 mmHg) developed by 60 min, continued to fall to 104 mmHg by 200 min and rose terminally to 118 mmHg. These values were higher than the control group, but were below those of the control period of the lidocaine group. Six -3H-glucose-derived Rd values were increased above their own control period at 60 min, but were approximately 55% lower than in the untreated group. Ra values were not significantly changed in the lidocaine-treated group resulting in a net glucose deficit which was more profound than in untreated pigs, whose Ra values did increase. The degree of hypoglycemia was more profound in lidocaine-treated pigs from 100-260 min, stabilizing at 29-37 mg/dl. Blood lactate (70 mg/dl) was above those of the control pigs (44 mg/dl) from 160 to 220 min. U-14C-glucose-derived glucose recycling was increased above the lidocaine group's preendotoxin control period and reached values twice those of the untreated pigs' endotoxin infusion period. Compared to their own control period and the untreated group's endotoxin infusion period, percentage lactate/glucose was decreased from 40 min on. Lidocaine treatment elicited modest improvements in systemic arterial blood pressure and reduced relative glucose utilization and gluconeogenesis, but in itself, was not a sufficient therapy for endotoxic shock in this model.

Acid-Base Equilibrium↗

PubMed1984

Tourette's syndrome and migraine.

Among 60 patients with Tourette's syndrome (TS), whose mean age was 11.9 years, migraine was prevalent in 26.6%. This figure is substantially greater than that reported for the general population of school-aged children (4.0% to 7.4%) or for two control groups consisting of children with seizure disorders (n = 72) and learning disabilities (n = 62). The prevalence rates for these two control groups were 11.3% and 8.0%, respectively. The hypothesis is offered that the coexistence of TS and migraine in a subgroup of children with TS may reflect a similar abnormality underlying both conditions; specifically, neurohumoral dysfunction involving serotonin metabolism.

Adolescent↗

PubMed2000

L-lactate inhibits L-cystine/L-glutamate exchange transport and decreases glutathione content in rat cultured astrocytes.

In several brain pathologies, the level of brain L-lactate increases. The stimulation of L-lactate production is a detrimental factor in promoting neuronal cell damage and astrocytic dysfunction. Astrocytic glutathione metabolism has an important role to protect brain cells against oxidative stress. In this study, effects of L-lactate on L-cystine uptake and glutathione level in rat-cultured astrocytes were examined. L-Lactate decreased the L-(35)S-cystine and Na(+)-independent L-(3)H-glutamate uptakes into astrocytes at the concentrations more than 2.5 mM. The L-lactate-induced decrease in L-(35)S-cystine uptake was neither affected by modification of extracellular pH nor mimicked by acetate, propionate and butyrate. The apparent Km value of the L-(35)S-cystine uptake was increased by L-lactate, while the Vmax was not changed. Astrocytic glutathione and nonprotein thiol content was decreased by incubation with 20 mM L-lactate for 48 hours (65% and 75% of control values, respectively). The decreases in astrocytic glutathione and nonprotein thiol content were restored to normal levels by withdrawal of L-lactate. These results suggest that L-lactate inhibits astrocytic L-cystine/L-glutamate exchangers and affects the glutathione contents.

Animals↗

PubMed1994

Perinotochordal connective sheet of gilthead sea bream larvae (Sparus aurata, L.) affected by axial malformations: an histochemical and immunocytochemical study.

BACKGROUND: Spinal malformations in adult teleosts occur under natural conditions and, more frequently, in culture exploitations. Skeletal deformities are linked with dysfunctions in collagen metabolism. We studied axial deviations appearing in early larval stages of cultured sea bream (Sparus aurata, L.). METHODS: To evaluate connective tissue components of normal and lordotic fish we used histochemistry (alcian blue, picrosirius-polarization, clorhydric orcein, fuchsin resorcin), immunohistochemistry (anti-collagen I, II, III, and IV), and specific enzymatic digestions. The results were evaluated by semiquantitative methods. RESULTS: Lordosis appeared before a vertebral column was developed, thus affecting the only skeletal structure present in the animal body, the notochord. At this stage the animal depends on the vitelline sac and an inflated swim-bladder is missing. The region of the curvature showed strong alterations in the arrangement of the muscle bundles and irregularities in notochord and perinotochordal collagen sheet. Histochemical and immunocytochemical analysis of the perinotochordal sheet revealed the presence of type II collagen, non-sulfated glycosaminoglycans, and elastic fibers in normal and lordotic specimens. Low collagen-proteoglycan interactions occurred in lordotic animals. CONCLUSIONS: Lordosis in Sparus aurata originated during embryonic development and was characterized by disorganized connective tissue and muscle bundles. No major differences in connective tissue constituents were seen with respect to normal specimens.

Animals↗

PubMed2002

Myocardial infarction following the combined recreational use of Viagra and cannabis.

Sildenafil citrate (Viagra, Pfizer, Inc., New York, N.Y.) is widely prescribed as a treatment for male erectile dysfunction. It is metabolized predominantly by the cytochrome P450 3A4 hepatic microsomal isoenzyme and effects can, therefore, be potentiated by such inhibitors. The vasodilatory effects of Viagra necessitate caution in its use in patients with cardiovascular disease and it is contraindicated in patients receiving nitrates. Previous literature has drawn attention to Viagra use and myocardial infarction. This paper reports the case of a young man who presented with a myocardial infarction after taking Viagra in combination with cannabis, a known inhibitor of the cytochrome P450 3A4 isoenzyme.

Adult↗

PubMed1978

Calcinosis in nonparathyroid malignant disease: an unusual case report and clinicopathologic review of 17 cases.

An unusual finding of systemic calcinosis in a patient with a nonparathyroid malignant neoplasm stimulated us to do a sclinicopathologic review of similar cases at our institution in the past seven years. Of 3,268 autopsies performed from 1968 to 1975, a total of 17 cases of calcinosis were found, 11 with solid tumors and 6 with hematopoietic neoplasms. Calcinosis was most prominent in the lung, kidney, heart, and stomach and was rarely discovered prior to death. Eighty-two percent of the patients had hypercalcemia and 53% had associated bony metastatic disease. Corticosteroid or phosphate treatment for the hypercalcemia may have contributed to the tissue deposition of calcium. Significant hepatic, renal, metabolic, and pulmonary dysfunctions were also associated with this disorder. Thirty-six percent of the patients had hypercalcemia without skeletal involvement; tumor-produced parathormone-like substances may be responsible for these calcium abnormalities. Calcinosis was a significant complication of neoplastic disease in these patients and contributed to morbidity and mortality.

Adolescent↗

PubMed2025

Absolute Quantification of Cellular and Cell-Free Mitochondrial DNA Copy Number from Human Blood and Urinary Samples Using Real Time Quantitative PCR.

Mitochondrial DNA copy number (mtDNA-CN) in human body fluids is widely used as a biomarker of mitochondrial dysfunction in common metabolic diseases. Here we describe protocols to measure cellular and/or cell free (cf)-mtDNA-CN in human peripheral blood and urine. Cellular mtDNA is located inside the mitochondria where it encodes key subunits of the respiratory complexes in mitochondria and is usually normalized with reference to the nuclear genome as the mitochondrial genome to nuclear genome ratio (Mt/N) in either whole blood, peripheral blood mononuclear cells (PBMCs), or whole urine. Cf -mtDNA is usually found outside of the mitochondria, often released following mitochondrial damage, can trigger inflammatory pathways, and is usually measured as mtDNA-CN per volume of the starting material. Here we describe how to (1) separate whole blood into PBMCs, plasma, and serum fractions and whole urine into urinary supernatant and pellet, (2) prepare DNA from each of these fractions, (3) prepare reference standards for absolute quantification, (4) carry out qPCR for either relative or absolute quantification from test samples, (5) analyze qPCR data, and (6) calculate the sample size to adequately power studies. The protocol presented here is suitable for high throughput use and can be modified to quantify mtDNA from other body fluids, human cells, and tissues.

Humans↗

PubMed1994

PET studies in progressive supranuclear palsy.

Functional imaging (PET and SPECT) can be used to non-invasively demonstrate the patterns of metabolic and dopaminergic dysfunction associated with progressive supranuclear palsy. In this chapter the findings of published functional imaging studies are reviewed and the value of PET for distinguishing between the various degenerative causes of parkinsonism is discussed.

Diagnosis, Differential↗

PubMed1993

Partial and complete de Toni-Debré-Fanconi syndrome after ifosfamide chemotherapy of childhood malignancy.

Ten out of 79 patients treated with ifosfamide (IFO) developed a complete (n = 2) or partial (n = 8) de Toni-Debré-Fanconi syndrome (RFS). All but one of these patients had been treated in addition with cisplatinum (CPL) or had undergone radiotherapy to the abdomen or nephrectomy as part of the overall treatment for malignancy. A detailed nephrological work-up of proximal tubular function showed decreased fractional phosphate and percent aminoacid reabsorption in 37.1 and 56.7% of cases, respectively, and the excretion of alpha 1-microglobulin and N-acetyl-beta-D-glucosaminidase was elevated in 44.4 and 23.5%. Glomerular function was well preserved in the majority of patients. Tubular dysfunction was confirmed by silver-stained SDS PAGE of urine which showed mostly low molecular weight proteinuria. CPL has been shown to result in renal magnesium loss and reduced glomerular filtration rate, and its toxicity clearly differs from IFO-mediated tubulopathy. Our data suggest that subclinical impairment of proximal tubular function was significantly increased by additional CPL therapy. We conclude that CPL may enhance IFO-mediated nephrotoxicity and that a substantial number of patients is at risk of developing persistent tubular dysfunction leading to metabolic bone disease.

Child↗

PubMed1982

Ogilvie's syndrome (acute colonic pseudo-obstruction): review of the literature (October 1948 to March 1980) and report of four additional cases.

Four additional cases of Ogilvie's syndrome (acute colonic pseudo-obstruction), representing the first cases described in Italy, are reported. The medical literature concerning the subject is also thoroughly reviewed. Ogilvie's syndrome is an acute massive dilatation of the large bowel without organic obstruction of the distal colon. Three hundred and fifty-one cases have been described in the literature to date. Eighty-eight per cent of the cases were associated with various extracolonic affections (metabolic and organ dysfunctions, postoperative and posttraumatic states, etc.). Twelve per cent of cases were not associated with known disorders and were defined as idiopathic. The pathophysiology of the syndrome is still unknown. Ogilvie, who first described the syndrome in 1948, suggested an imbalance between the sympathetic and parasympathetic innervation of the colon: this neurogenic hypothesis has been shared by other authors, although explanations may differ slightly. The clinical and radiologic picture closely resembles mechanical obstruction of the large bowel. The most marked dilatation usually takes place in the right colon and cecum: if the distended cecum reaches a diameter larger than 9 to 12 cm, perforation is likely to occur; if perforation occurs, the mortality rate increases from 25 to 31 per cent to about 43 to 46 per cent. If conservative management fails to control the dilatation and cecal rupture is impending or suspected emergency surgery is indicated, the surgical procedure of choice is dictated by the general conditions of the patient as well as by the intestinal findings: operation may consist of cecostomy, colostomy, or right hemicolectomy or simply emptying the bowel.

Adult↗

PubMed1996

Three- to five-dimensional biomedical multisensor imaging for the assessment of neurological (dys) function.

This report describes techniques and protocols implemented at the Geneva Canton University Hospitals (HUG) for the combination of various biomedical imaging modalities and sensors including electromagnetic tomography, to study, assess, and localize neurological (dys) function. The interest for this combination stems from the broad variety of information brought out by (functional) magnetic resonance imaging, magnetic resonance spectroscopy, computed tomography, single-photon emission tomography, positron emission tomography, and electromagnetic tomography. Combining these data allows morphology, metabolism, and function to be studied simultaneously, the complementary nature of the information from these modalities becoming evident when studying pathologies reflected by metabolic or electrophysiologic dysfunctions. Compared with other current multimodality approaches, the one at the HUG is totally compatible with both clinical and research protocols, and efficiently addresses the multidimensional registration and visualization issues. It also smoothly integrates electrophysiology and related data as fully featured modalities.

Computer Graphics↗

PubMed1999

Long-term measurements of energy expenditure in severe burn injury.

The objective of this study was to evaluate resting energy expenditure (REE) in spontaneously breathing and artificially ventilated burn patients during the entire intensive care period. In 27 patients with 51 +/- 20% body surface area burned (BSAB) the REE was determined via indirect calorimetry. Three groups were formed according to the mortality prognosis index of Zawacki et al. In groups A, B, and C the predicted mortality rates were <20%, 20% to 80%, and >80%, respectively. The frequency of acute respiratory distress syndrome (ARDS), sepsis, renal failure, and mortality increased from group A toward group C. The REE test revealed wide individual variation and was usually overestimated by all tested formulas. The mean REE was comparable in groups A, B, and C during the first 20 days (49 +/- 16% vs. 59 +/- 21% vs. 57 +/- 18% above the REE calculated by the Harris-Benedict equation, or HBEE). The REE of patients in groups A and B declined after this period, whereas the long-term ventilated patients in the prognostically unfavorable group C showed a high REE up to the 45th day, usually accompanied by severe organ dysfunction and major metabolic disorders. During this time a nutritional regimen meeting the actual REE could not be achieved. In the clinical situation when indirect calorimetry is not available, REE can be stated to be 50% to 60% above HBEE in patients with >20% BSAB for at least 20 days. Expecting a stable clinical course in patients with a predicted mortality of <20% (group A), oral nutrition usually seems sufficient after a short period of artificial nutritional support (1 week). Patients with a predicted mortality of more than 20% have a complication-burdened clinical course and a prolonged period of ventilation (groups B and C). These patients need parenteral and enteral nutrition for at least 20 days after trauma to prevent severe malnutrition.

Adolescent↗

PubMed2002

Amino acid imbalance early in septic encephalopathy.

OBJECTIVE: To evaluate plasma amino acid concentrations and markers of inflammation in the early stage and the course of septic encephalopathy. DESIGN: Prospective, case series of patients with well-defined septic encephalopathy. SETTING: Surgical department and intensive care unit of a university hospital. PATIENTS: Seventeen patients with sepsis according to the ACCP/SCCM consensus conference criteria and encephalopathy based on neuropsychological tests, compared to a control group undergoing uncomplicated thoracic surgery. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: SOFA score, blood samples for plasma amino acids, procalcitonin and interleukin-6. Sepsis was determined to be the cause of encephalopathy in 14 of the 17 patients. Six patients developed septic shock, four died within the study period of 28 days. Within 12 h of the onset of septic encephalopathy, mean values of PCT and IL-6 were elevated ( p<0.001) and the amino acids unbalanced (the ratio of branched-chain to aromatic amino acids was decreased, p<0.001). During the course of sepsis the decreased amino acid ratio was significantly, but moderately, correlated with elevated PCT and IL-6 levels. On study days when PCT was higher than 2 ng/ml, the amino acid ratio was significantly lower. In no patient was severe liver dysfunction seen. CONCLUSIONS: Metabolic disturbances with changes in amino acid levels can occur early in septic patients, without serious liver abnormalities. The present data suggest a possible role of amino acids in the pathogenesis of septic encephalopathy.

Amino Acids↗

PubMed2006

Video-assisted gastrostomy in infants less than 1 year.

The objectives of this study were to report our experience with the laparoscopic video-assisted gastrostomy technique in infants operated during their first year of life. A total of 53 infants (35 males, 18 females) aged 6 +/- 3 months, varying from 3 weeks to 11 months, underwent video-assisted gastrostomy. They were prospectively followed up. Included are infants with neurological dysfunction, chromosomal anomalies, metabolic disorders, cardiac anomalies or respiratory insufficiency. All the infants were operated under general and local anaesthesia. Gastrostomy tube feeding began within 4 h after the operation. The infants were followed with a scheduled control at 1 and 6 months postoperatively documenting complications and weight gain. The main outcome measure was the number and type of complications as well as weight gain using the age-adjusted Z-score of weight to normalize the data relative to a reference population. The weight before and 6 months after the video-assisted gastrostomy was 5.5 +/- 1.6 and 8.5 +/- 1.6 kg, respectively. The Z-score increased significantly (P < 0.001) from -2.7+/-1.5 to -1.7 +/- 1.0. This illustrates the postoperative weight gain and catch-up. Short and long-term complications included minor local wound infection, leakage around the gastrostomy tube and granuloma, but no severe complications. Our results encourage the use of video-assisted gastrostomy as a safe technique to provide a route for long-term nutritional support even in infants less than 1 year.

Female↗

PubMed2003

Psychoneuroendocrine correlates of secondary amenorrhea.

Functional hypothalamic amenorrhea is a common, non-organic and theoretically reversible form of anovulation due to reduced hypothalamic GnRH drive. Numerous studies suggest that this altered hypothalamic homeostasis is caused by a synergism between psychogenic challenge, promoted in part by dysfunctional attitudes, and metabolic compromise induced by undernutrition and overexercise. The recent growing interest in psychiatric comorbidity underlines the importance of reconsidering the boundaries between psychological disorders and somatic conditions. That not withstanding, it is mandatory in gynecological endocrinology to explore the issue of secondary amenorrhea from a psychoneuroendocrine perspective in order to devise biopsychosocial interventions which address the individual distress. In this brief review we will try to critically discuss the issue providing evidences from personal studies as clues for better understanding the extent of the complex psychoneuroendocrine network controlling menstrual function.

Amenorrhea↗

PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗

PubMed2007

In vivo functions of mitogen-activated protein kinases: conclusions from knock-in and knock-out mice.

Multicellular organisms achieve intercellular communication by means of signalling molecules whose effect on the target cell is mediated by signal transduction pathways. Such pathways relay, amplify and integrate signals to elicit appropriate biological responses. Protein kinases form crucial intermediate components of numerous signalling pathways. One group of protein kinases, the mitogen-activated protein kinases (MAP kinases) are kinases involved in signalling pathways that respond primarily to mitogens and stress stimuli. In vitro studies revealed that the MAP kinases are implicated in several cellular processes, including cell division, differentiation, cell survival/apoptosis, gene expression, motility and metabolism. As such, dysfunction of specific MAP kinases is associated with diseases such as cancer and immunological disorders. However, the genuine in vivo functions of many MAP kinases remain elusive. Genetically modified mouse models deficient in a specific MAP kinase or expressing a constitutive active or a dominant negative variant of a particular MAP kinase offer valuable tools for elucidating the biological role of these protein kinases. In this review, we focus on the current status of MAP kinase knock-in and knock-out mouse models and their phenotypes. Moreover, examples of the application of MAP kinase transgenic mice for validating therapeutic properties of specific MAP kinase inhibitors, and for investigating the role of MAP kinase in pathogen-host interactions will be discussed.

Animals↗

PubMed2005

Cardiac surgery for a patient with familial lecithin: cholesterol acyltransferase deficiency.

A 62-year-old female with familial lecithin: cholesterol acyltransferase (LCAT) deficiency was subjected to cardiac surgery consisting of mitral valve repair, tricuspid valve annuloplasty, and left atrium plication, under cardiopulmonary bypass. Familial LCAT deficiency is a very rare disease with clinical features including corneal opacity, hemolytic anemia, and renal failure. Our patient manifests partial LCAT activity and no renal failure. Patients with LCAT deficiency have fragile red blood cells, renal dysfunction, and disturbed metabolism of platelet-activating factor. To date, no record of cardiac surgery on patients with LCAT deficiency has been reported. Thus, we present the result of this experience to share what we learned about this complicated and rare disease.

Cardiopulmonary Bypass↗