Genes required for fructose metabolism are expressed in Purkinje cells in the cerebellum

Since 1967, fructose has become the primary commercial sweetener in the food industry. Large amounts of fructose can be toxic and have been correlated with atherosclerosis, malabsorption, hyperuricemia, lactic acidosis, and cataracts. To understand the deleterious and critical role(s) fructose plays in normal metabolism, it is essential to know how and where fructose is metabolized. The fructose transporter, GLUT5, and the specialized enzymes ketohexokinase, aldolase, and triokinase comprise the well-defined fructose-specific metabolic pathway found in liver, kidney, and small intestine. It is estimated that 50-70% of ingested fructose is metabolized in these tissues; where and how the remaining 30-50% is metabolized is not well defined. Prediction of tissues capable of metabolizing fructose via this pathway was done using expressed sequence tags (ESTs) in Unigene and a gene-specific virtual northern blot (VNB) algorithm. Unigene and VNB combined correctly predicted the expression of the genes required for fructose metabolism in liver, kidney, and small intestine. Both methods indicated brain, breast, lymphocytes, muscle, placenta, and stomach additionally express this set of genes. Expression of the genes for GLUT5 (glut5) and ketohexokinase (khk) in neurons was validated by immunohistochemistry and RNA in situ hybridization, respectively. Using stringent controls, clear expression of glut5 and khk was localized to Purkinje cells in the cerebellum. Cerebellum was used to oxidize fructose to carbon dioxide. Together, these data suggest that these neurons in the brain are able to utilize fructose as a carbon source.     

Inflammatory process as a determinant factor for the degeneration of substantia nigra dopaminergic neurons

Summary. The specific degeneration of dopaminergic neurons in the substantia nigra (SN) is a pathological hallmark of Parkinsons disease (PD). Although the cause of chronic nigral cell death in PD and its underlying mechanisms remain elusive, substantial involvement of inflammatory events has been postulated since inflammatory features have been described in parkinsonians CNS tissue. We have developed an animal model of dopaminergic neurons degeneration by the single intranigral injection of lipopolysaccharide (LPS), an inflammatory compound. This single injection produced the induction of inflammatory process with the activation of microglia along with the specific degeneration of dopaminergic neurons in the SN without affecting neither other neurotransmitter systems nor other structures of the CNS. Dexamethasone, a potent anti-inflammatory drug preventing many of the features characterizing pro-inflammatory glial activation, prevented the loss of dopaminergic cells. We also discuss other inductors of inflammatory process in relationship to the dopaminergic degeneration in the SN.     

Acetaminophen overdose in pregnancy

Acetaminophen (APAP) is the most common drug overdose in pregnancy. Available data regarding APAP overdose in pregnancy is limited to case reports and a small prospective case series. APAP has been demonstrated to cross the placenta and in toxic doses may harm the fetal and maternal hepatocytes. Fetal hepatocytes metabolize APAP into both active and toxic metabolites. These toxic metabolites may cause fetal hepatic necrosis. N-acetylcysteine (NAC) has also been demonstrated to cross the placenta and may bind toxic metabolites in both the mother and the fetus. Limited data suggest that the majority of morbidity and mortality from APAP overdose can be averted by initiation of NAC within the first 16 hours of ingestion and possibly even later. NAC may be safely administered during pregnancy and should be initiated early after APAP overdosage. The literature was reviewed through the use of OvidMEDLINE database, encompassing 1966 to the present. Searches were conducted using the key words acetaminophen, paracetamol, N-acetylcysteine, overdose, and hepatotoxicity. The search was further refined by selecting articles that contained these search words together with the key word pregnancy. Only English language papers were reviewed. Articles were selected on the basis of relevance to the topic. Pertinent citations found in the selected articles were also reviewed.     

Knee arthrodesis with the Wichita fusion nail

We reviewed 32 patients who all had knee arthrodesis performed after failed knee replacement. The minimum clinical follow-up was 1 year. The arthrodesis was performed by means of the Wichita fusion nail in 11, by external fixation in 15 cases, by plating in three and by intramedullary nailing in three. The mean patient age was 68.6 years. When the Wichita nail was used, fusion was achieved in ten out of 11 cases after a mean period of 4.5 (3–7) months. Of the remaining 21 patients, fusion was only achieved in 11 cases after a mean period of 6.5 (4.5–10) months.

---

Résumé Nous avons examiné 32 malades, avec un suivi minimum dun an, après arthrodèse du genou pour échec de remplacement prothétique. Larthrodèse a été exécutée au moyen dun clou de Wichita dans 11 cas, par fixation externe dans 15 cas, par plaque vissée dans trois cas en plaquant et par enclouage centromédullaire dans trois cas en. Lâge moyen des patients était 68.6 années. Quand le clou Wichita a été utilisé la fusion a été réalisée dans 10 cas sur 11 après une période moyenne de 4.5 (3–7) mois. Chez les 21 autres malades, la fusion a été réalisée 11 fois, après une période moyenne de 6.5 (4.5–10) mois.

     

Preoperative blood test results and type of fracture as transfusional risk factors in patients older than 65 years with trochanteric hip fracture

OBJECTIVE: To determine the effect of risk factors for allogenic blood transfusion in surgery for trochanteric hip fractures. PATIENTS AND METHODS: A retrospective study of all the trochanteric hip fracture patients older than 65 years who underwent surgery to repair trochanteric hip fracture related to osteoporosis in 2000 and 2001 in a regional hospital. Data recorded were age; gender; type of fracture (international AO classification); level of anesthetic risk (ASA classification); hemoglobin concentration and hematocrit upon admission, on the day of surgery and 2 days later; time elapsing between admission and surgery; blood transfusion and blood product use. RESULTS: One hundred two patients (29 men and 73 women) with trochanteric hip fractures were studied. Mean (+/- SD) patient age was 82.9 +/- 8.8 years (range, 65-99 years). Upon admission, mean hemoglobin was 123 +/- 18.1 g/L (range, 56-154 g/L), hematocrit was 37% +/- 5% (range, 10%-40%). Time elapsing until surgery was 3.5 +/- 1.6 days (range, 0-8 days). Admission hemoglobin concentration was lower in patients who required transfusion (116 g/L) than in patients who did not (133 g/L) (P < 0.001). Logistical regression analysis identified only AO classification of fracture type (P < 0.05) and admission hemoglobin concentration (P < 0.001) as independent risk factors for transfusion. CONCLUSIONS: The hemoglobin level at admission and the trochanteric fracture type bear a relation to transfusion needs. These results suggest that in elderly patients we should improve hemoglobin levels and initiate blood salvage measures in order to reduce the need for allogenic blood transfusion, with its inherent risks.     

Impact of Surgically-Induced Weight Loss on Respiratory Function: A Prospective Analysis

Background: Morbid obesity (MO) causes several degrees of respiratory impairment that may resolve after weight reduction. The aims of the present study were to investigate the frequency of respiratory impairment in a selected cohort of morbidly obese patients with BMI 40-50 kg/m² with no respiratory symptoms and to evaluate the impact of surgically-induced weight loss on respiratory function. Methods: Prospective analysis of respiratory impairment was conducted before surgery and 1 year after surgery in a cohort of patients with MO who underwent vertical banded gastroplasty (VBG). 30 consecutive patients with MO who underwent VBG (14 open and 16 laparoscopic) in a 1-year period were studied. Respiratory function tests, arterial blood gases and hemoglobin were obtained in all patients before and 1 year after VBG. Results: Results were analyzed using the Wilcoxon signed-rank test and Spearman for variables without normal distribution. Mean age was 35±8 years; there were 3 males and 27 females. BMI was 44±4 kg/m² before surgery and 32±4 kg/m² at 1-year follow-up. By respiratory function tests, the diagnosis of obstructive disease was made before surgery in 4 patients and a restrictive disorder was identified in 4 additional patients. Evidence of pulmonary disease was absent in all patients 1 year after surgery. Forced vital capacity, inspiratory and expiratory forces, tidal volume, SaO₂, and PaCO₂ significantly improved after weight reduction. Conclusion: Surgically-induced weight loss significantly improves pulmonary function.     

Molecular characterization of isoniazid-resistant Mycobacterium tuberculosis clinical strains isolated in the Philippines

The prevalence of mutations in the katG, inhA and oxyR-ahpC genes of isoniazid (INH)-resistant Mycobacterium tuberculosis isolates in the Philippines were determined. Of 306 M. tuberculosis isolates studied, 81 (26.5%) exhibited INH-resistance. Forty-four strains (54.3%) had mutations in the katG gene, eighteen strains (22.2%) had mutations in the putative inhA locus region, seven had mutations in both regions and five strains had mutations in the oxyR-ahpC operon. Only seven strains had no mutations. A total of 71 of the 81 (87.6%) resistant strains and 65 of the 72 (90.3%) INH sensitive randomly selected strains showed amino acid substitution in codon 463 (Arg to Leu) (88.9%). This fact supports the hypothesis that mutations at codon 463 are independent of INH-resistance and are linked to the geographical origins of the strains.     

Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies.

PURPOSE: This phase I study was undertaken to define the toxicity, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD), and clinical activity of CI-1040, a small-molecule inhibitor of the dual-specificity kinases MEK(mitogen-activated protein kinase kinase) -1 and MEK2 , in patients with advanced malignancy. PATIENTS AND METHODS: CI-1040 was tested in multiple daily dosing frequencies administered for 21 days repeated every 28 days leading ultimately to continuous administration, and effect of food on absorption was tested. Single dose and steady-state pharmacokinetics were assessed during cycle 1 and phosphorylated extracellular receptor kinase (pERK) levels were assessed in WBCs and also in tumor tissue from selected patients. RESULTS: Seventy-seven patients received CI-1040 at dose levels ranging from 100 mg QD to 800 mg tid. Grade 3 asthenia was dose limiting at the highest dose level tested, 800 mg tid administered with food. Ninety-eight percent of all drug-related adverse events were grade 1 or 2 in severity; most common toxicities included diarrhea, asthenia, rash, nausea, and vomiting. Plasma concentrations of CI-1040 and its active metabolite, PD 0184264, increased in a less than dose proportional manner from 100 to 800 mg QD. Administration with a high-fat meal resulted in an increase in drug exposure. The MTD and recommended phase II dose was 800 mg BID administered with food. Sixty-six patients were assessable for response. One partial response was achieved in a patient with pancreatic cancer and 19 patients (28%) achieved stable disease lasting a median of 5.5 months (range, 4 to 17 months). Inhibition of tumor pERK (median, 73%; range, 46% to 100%) was demonstrated in 10 patients. CONCLUSION: CI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study.