HO Group Research Articles

Insulin Action in Adipose Tissue and Muscle in Hypothyroidism

Although insulin resistance in thyroid hormone excess is well documented, information on insulin action in hypothyroidism is limited. To investigate this, a meal was given to 11 hypothyroid (HO; aged 45 +/- 3 yr) and 10 euthyroid subjects (EU; aged 42 +/- 4 yr). Blood was withdrawn for 360 min from veins (V) draining the anterior abdominal sc adipose tissue and the forearm and from the radial artery (A). Blood flow (BF) in adipose tissue was measured with 133Xe and in forearm with strain-gauge plethysmography. Tissue glucose uptake was calculated as (A-V)glucose(BF), lipoprotein lipase as (A-V)Triglycerides(BF), and lipolysis as [(V-A)glycerol(BF)]-lipoprotein lipase. The HO group had higher glucose and insulin levels than the EU group (P < 0.05). In HO vs. EU after meal ingestion (area under curve 0-360 min): 1) BF (1290 +/- 79 vs. 1579 +/- 106 ml per 100 ml tissue in forearm and 706 +/- 105 vs. 1340 +/- 144 ml per 100 ml tissue in adipose tissue) and glucose uptake (464 +/- 74 vs. 850 +/- 155 micromol per 100 ml tissue in forearm and 208 +/- 42 vs. 406 +/- 47 micromol per 100 ml tissue in adipose tissue) were decreased (P < 0.05), but fractional glucose uptake was similar (28 +/- 6 vs. 33 +/- 6% per minute in forearm and 17 +/- 4 vs. 14 +/- 3% per minute in adipose tissue); 2) suppression of lipolysis by insulin was similar; and 3) plasma triglycerides were elevated (489 +/- 91 vs. 264 +/- 36 nmol/liter.min, P < 0.05), whereas adipose tissue lipoprotein lipase (42 +/- 11 vs. 80 +/- 21 micromol per 100 ml tissue) and triglyceride clearance (45 +/- 10 vs. 109 +/- 21 ml per 100 ml tissue) were decreased in HO (P < 0.05). In hypothyroidism: 1) glucose uptake in muscle and adipose tissue is resistant to insulin; 2) suppression of lipolysis by insulin is not impaired; and 3) hypertriglyceridemia is due to decreased clearance by the adipose tissue.

Practical aldol reaction of trimethylsilyl enolate with aldehyde catalyzed by N-methylimidazole as a Lewis base catalyst

Aldol reaction of trimethylsilyl enolate with aldehyde proceeded in the presence of a catalytic amount of a Lewis base, N-methylimidazole, and lithium chloride in DMF at room temperature. Not only aryl aldehyde but also alkyl aldehyde provided the aldol product in satisfactory yields. The reaction was mild enough to apply to the aldehyde having HO, AcO, THPO, TBDMSO, MeS, pyridyl or olefinic group. Microwave irradiation accelerated the reaction.

Impact of Holmium-DOTMP on Transplant Outcomes. Results of a Retrospective Single Institution Analysis.

Background:166Holmium-DOTMP is a beta emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Phase I/II trials have shown feasibility and tolerability when combined with a standard conditioning regimen of melphalan with or without total-body irradiation (TBI) in pts with multiple myeloma (MM) undergoing autologous stem cell transplantation (SCT).Purpose: To define the potential impact of 166Holmium-DOTMP (HO) in combination with melphalan when compared to a standard conditioning regimen of melphalan 200 mg/m2 (M200) in MM patients undergoing auto SCT.Methods: We performed a retrospective review of transplant outcomes among patients with MM who received an auto SCT between 1/98-12/01 with either M200 or a melphalan-HO combination and were in a 1ry refractory or 1st remission consolidation state. Univariate analysis was performed for response, survival and event free survival.Results: 104 pts were identified. Patient characteristics are summarized in Table 1. In brief the HO group had a higher percentage of patients with IgA disease, otherwise there were no siginificant differences in prognostic factors among the groups. Transplant outcomes are summarized in Table 2. The HO group had a trend towards a higher conversion to CR rate (51% vs 32%) for all patients, (23% vs 12.5%) for 1ry refractory patients and similar OS rates and a higher NRM rate of 12% vs 3% when compared to MEL200. When the analysis was limited to patients receiving <2400 mCi the HO group had a trend towards longer PFS (33 months vs 24 months) with no difference in NRM rates. The OS rate at 5 yrs was 54% for the HO group vs 43% for the MEL200 group, among the 21 patients in the HO group receiving <2400 mCi the 5 yr OS was 61% (Figure 1).Conclusion: 166Holmium-DOTMP in combination with high dose melphalan can result in higher CR rates than melphalan 200 mg/m2 alone, when given in optimal doses (<2400 mCi) the results seem to be superior and the toxicities are minimal. Targeted skeletal radiotherapy with 166Holmium-DOTMP in combination with melphalan 200 mg/m2 is safe and effective and should be further studied in Phase III trials in all patients with MM undergoing autologous SCT, based on these data other methods of targeted skeletal radiotherapy should also be pursued.Patient CharacteristicsHO <2400 mCiHO ≥ 2400 mCiMelphalan 200p MEL200 vs HON212063Median Age52 (45–61)53 (36–64)55 (35–69)NSIgA Type33%40%14%.03Median B2M @ Dx3.153.153.5NSDurie Salmon III43%55%67%NSNumber with Δ13003NSCR/PR @ SCT5%/57%5%/70%6%/68%NS1ry Refractory38%25%25%NSTransplant OutcomesHO <2400 mCiHO ≥ 2400 mCiMEL200MEL 200 vs HOORR/CR conversion95%/55%90%/48%92%/32%NS/.06NRM5%20%3%.07Median OSNR31 months52 monthsNSMedian EFS30 months23 months19 months.3

Diagnostic accuracy and reproducibility in the interpretation of Ottawa ankle and foot rules by specialized emergency nurses

Objectives The ED is often confronted with long waiting periods. Because of the progressive shortage in general practitioners, further growth is expected in the number of patients visiting the ED without consulting a general practitioner first. These patients mainly present with minor injuries suitable for a standardized diagnostic protocol. The question was raised whether these injuries can be treated by trained ED nurses (specialized emergency nurses [SENs]). The aim of this study was to evaluate the diagnostic accuracy and reproducibility of SENs in assessing ankle sprains by applying the Ottawa Ankle Rules (OAR) and Ottawa Foot Rules (OFR). Methods In a prospective study, all ankle sprains presented in the ED from April to July 2004 were assessed by both a SEN and a junior doctor (house officer [HO]) randomized for first observer. Before the study, SENs were trained in applying OAR and OFR. In all patients, radiography was performed (gold standard). The diagnostic accuracy for the application of OAR and OFR was calculated for both groups and was compared using z statistics. Furthermore, from the paired results, reproducibility was calculated using κ statistics. Results In total, 106 injuries were assessed in pairs, of which 14 were ultimately found to concern acute fractures (prevalence, 13%). The sensitivity for the SEN group was 0.93 (95% confidence interval [CI], 0.64-1.00) compared with 0.93 (95% CI, 0.64-1.00) for the HO group (no significance [ns]). The specificity of the nurses was 0.49 (95% CI, 0.38-0.60) compared with 0.39 (95% CI, 0.29-0.50) for the doctors (ns). The positive predictive value for the SEN group was 0.22 (95% CI, 0.13-0.35) compared with 0.19 (95% CI, 0.11-0.31) for the HO group (ns). The negative predictive value for the nurses was 0.98 (95% CI, 0.87-1.00) compared with 0.97 (95% CI, 0.84-1.00) for the doctors (ns). The interobserver agreement for the OAR and OFR subsets was κ = 0.38 for the lateral malleolus; κ = 0.30, medial malleolus; κ = 0.50, navicular; κ = 0.45, metatarsal V base; and κ = 0.43, weight-bearing. The overall interobserver agreement for the OAR was κ = 0.41 and κ = 0.77 for the OFR. Conclusion Specialized emergency nurses are able to assess ankle and foot injuries in an accurate manner with regard to the detection of acute fractures after a short, inexpensive course.

Induced hypothermia as a new approach to lung rest for the acutely injured lung*

To investigate whether low-frequency ventilation during hypothermia could attenuate lung injury associated with endotoxin and mechanical ventilation. : Experimental animal study. University-affiliated animal laboratory. Forty-eight Sprague-Dawley rats. : Lipopolysaccharide was administered to rats intratracheally to induce acute lung injury. After 1 hr of this treatment, animals were assigned to normothermia-only (NO, rectal temperature 37 degrees C, ventilatory frequency 90/min), normothermia-lung rest (NR, 37 degrees C, 45/min), hypothermia-only (HO, 27 degrees C, 90/min), or hypothermia-lung rest (HR, 27 degrees C, 45/min). After 1 hr of injurious ventilation, the lungs of the rats were removed for bronchoalveolar lavage and histologic examination. Compared with the normothermia groups (NO, NR), the neutrophil counts (per milliliter) (NO, 7708 +/- 5704; NR, 10,479 +/- 11,152; HO, 1638 +/- 955; HR, 805 +/- 591) and interleukin-1beta levels (pg/mL) (1180 +/- 439, 1081 +/- 652, 620 +/- 426, 420 +/- 182, respectively) in the bronchoalveolar lavage fluid, the wet-to-dry lung weight ratios (6.0 +/- 0.4, 5.7 +/- 0.4, 5.6 +/- 0.2, 5.2 +/- 0.2, respectively), and histologic acute lung injury scores (8.3 +/- 2.7, 10.4 +/- 3.1, 3.5 +/- 2.1, 3.1 +/- 2.2, respectively) of the hypothermia groups (HO, HR) were lower (all p < .001). Compared with the HO group, the neutrophil counts and protein content (HO, 1367 +/- 490 mug/mL vs. HR, 831 +/- 369 mug/mL) in the bronchoalveolar lavage fluid, the serum lactate dehydrogenase levels (units/mL) (9.1 +/- 3.6 vs. 5.3 +/- 1.5), and the wet-to-dry lung weight ratios of the HR group were lower (all p < .05). Reduction of ventilatory frequency in conjunction with hypothermia attenuated many variables of acute lung injury in rats. Use of hypothermia could be exploited as a new approach to lung rest for the ventilatory management of the acutely injured lung.

Peri-Interactions in naphthalenes, 13 8-Dimethylamino-naphth-1-yl carbinols as model systems for potential N→Si/P interactions

In (8-dimethylamino-naphth-1-yl) (‘DAN’) carbinols DAN–C(OH)R 1R 2, the N atom can approach the HO group unto N⋯H-O hydrogen bond distance only when the steric conditions are favourable. The energy gain of such N⋯H–O interactions is insufficient to force R 1 and R 2 into otherwise unfavourable conformations. The geometry of the naphthalene may cause N, O and C atoms to reside in positions similar to those typical for hydrogen bonds though no N⋯H–O and N⋯H–C hydrogen bonds may actually be involved. By analogy, it seems unlikely that in peri-donor/acceptor substituted naphthalenes D–C 10H 6–A dative interactions (D→A) of similar or less energy as such N⋯H-O interactions can interfere with the geometry conserving forces of naphthalene and the steric effects of the peri substituents.

Molecular electronics

Current work in molecular electronics usually addresses molecular junction electronic transport properties, where the molecule can be viewed as a barrier for incoming electrons. This is the fundamental Landauer idea of “conduction as scattering” generalized to metal/single molecule/metal molecular nanojunction structures. The experimental contributions from the Gourdon and Hersam groups focus on the tunneling process in molecular transport junctions, using powerful and elegant techniques involving both demanding single-molecule junction synthesis and scanning tunneling microscopy and spectroscopy. The paper by Ho's group extends these experimental methods to examine vibronic components in the STM-geometry conductance, using precisely engineered surface structures. The contribution by Fisher and Ness addresses those inelastic effects in junction transport from a theoretical point of view. The papers from the Mayor and Kushmerick groups address such transport issues as fluctuation and vibronic features of molecular electronic wires by using break-junction and monolayer test beds.

Peroxisome Proliferation in Liver of Rats Fed Oxidized Frying Oil

Oxidized frying oil (OFO) activates peroxisome proliferator-activated receptor a (PPAR alpha) in vitro and in vivo. As most PPARalpha activators are also peroxisome proliferators (PP), this study was aimed at exploring whether OFO induces peroxisome proliferation in the liver of rats. Four groups of male weanling Sprague-Dawley rats were fed the following diets for 6 wk: a basal diet containing 5 g/100 g fresh soybean oil (LSB), high-fat diets containing 20 g/100 g of fresh soybean oil (HSB as a control). OFO (HO) or fish oil (HF, as a positive control). Hepatomegaly and peroxisome proliferation in the liver of the HO group of rats were higher than those of the HF group. In addition, the acyl-CoA oxidase (ACO) activity, as well as cytochrome P450 4A (CYP4A) protein content in the livers of the HO group were 6 fold those of the HSB group, but were 2.5 fold in those of the HF group. These results indicated that dietary OFO induced typical responses to PPARalpha signaling. Moreover. as a dietary source, the OFO prepared under our frying conditions appears to be a more potent peroxisome proliferator than fish oil.

Theoretical studies on the mode of inhibition of ribonucleotide reductase by 2'-substituted substrate analogues.

Several 2'-substituted-2'-deoxyribonucleotides are potent time-dependent inactivators of the enzyme ribonucleotide reductase (RNR), which function by destructing its essential tyrosil radical and/or by performing covalent addition to the enzyme. The former leads to inhibition of the R2 dimer of RNR and the latter to inhibition of the R1 dimer. Efforts to elucidate the mechanism of inhibition have been undertaken in the last decades, and a general mechanistic scheme has emerged. Accordingly, two alternative pathways lead either to the inhibition of R1 or R2, for which the 2'-chloro-2'-deoxynucleotides serve as the model for the inhibition of R1 and the 2'-azido-2'-deoxynucleotides the model for the inhibition of R2. However, the underlying reason for the different behavior of the inhibitors has remained unknown until now. Moreover, a fundamental mechanistic alternative has been proposed, based on results from biomimetic reactions, in which the 2'-substituents would be eliminated as radicals, and not as anions, as previously assumed. This would lead to further reactions not predicted by the existing mechanistic scheme. To gain a better understanding we have performed high-level theoretical calculations on the active site of RNR. Results from this work support the general Stubbe's paradigm, although some changes to that mechanism are necessary. In addition, a rational explanation of the factors that determine which of the dimers (R1 or R2) will be inactivated is provided for the first time. It has been demonstrated also that the 2'-substituents are indeed eliminated as anions, and not as radicals. Biomimetic experiments have led to different results because they lack a basic group capable of deprotonating the 3'-HO group of the substrate. It has been found here that the chemical character of the leaving group (radical or anionic) can be manipulated by controlling the protonation state of the 3'-HO group.

Organofluorine compounds and fluorinating agents: Part 28. New perfluoroalkyl substituted chiral mesogens

The perfluorohexyl-aryl-thioethers 3 and 4, building blocks for the synthesis of the chiral target mesogens 12– 15, were prepared by dithionite-mediated S-perfluoroalkylation of the p-substituted thiophenols 1 and 2. The phenolic HO group of 3 was O-glucosylated with pentaacetyl- d-glucopyranose to 5 followed by deacetylation forming the tetrol 6 and by acetalizing with 4-(4-perfluorohexylsulfanyl-benzoyloxy)-benzaldehyde-dimethylacetal ( 8) generating the dihydroxy-intermediate 9. The latter contains two perfluorohexylthio chains. Alternatively, the dimethylacetal 8 was linked to p-octylphenyl-β- d-glucopyranoside ( 10) giving the mixed octyl/perfluorohexyl substituted p-octylphenyl-4,6- O-[4′-(4″-perfluorohexylsulfanyl)-benzoyloxy]-benzylidene-β- d-glucopyranoside (11). Compound 8 was obtained via esterification of 4 with p-hydroxy-benzaldehyde to 4-(4-perfluorohexylsulfanyl-benzoyloxy)-benzaldehyde ( 7). Finally, the diols 9 and 11 were dehydroxylated to 12 and 13 followed by hydrogenation yielding 14 and 15, respectively. Tetrol 6, diols 9, 11 and the non-amphiphilic compounds 7, 12– 15 are thermotropic liquid crystals.

Techniques for STM-IETS Measurement

Inelastic tunneling spectroscopy (IETS) combined with scanning tunneling microscopy (STM) has attracted attentions since Wilson Ho group published clear experimental results by use of specially designed STM instruments. Although the results of STM-IETS have clearly shown the vibration features of molecules, their behavior is case sensitive and not straight forward unlike the data from conventional IETS measurements. We believe that accumulation of STM-IETS data on various molecules and surfaces are critical for the further development of this technique. In this context it is quite important to evaluate that commercially available STM machines are capable of obtaining such vibrational information. In this paper, our recent STM-IETS system using a commercially available STM is introduced, and the key issues for the successful measurement of STM-IETS are described. In addition of a single point STM-IETS measurement, we show mapping of vibrational feature using conventional software, which can contribute to the understanding of the mechanism and future chemical analysis.

Phenotypic study of peripheral blood leucocytes in HTLV-I-infected individuals from Minas Gerais, Brazil.

The human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) associated with the HTLV-I is a well-defined clinical-pathological entity in which the virus and host immune responses contribute to the pathological mechanism. In this study, flow cytometric analysis of whole peripheral blood leucocytes (PBL) was performed to evaluate the immunological status of HTLV-I-infected individuals in an effort to better understand the role of the immune system in the development of HAM/TSP. We have evaluated three groups of infected patients including asymptomatic (AS = 18), ambulatory/oligosymptomatic (AM = 14) and hospitalized HAM/TSP individuals (HO = 42). Noninfected healthy blood donors were used for the control group (NI = 32). Our results demonstrated that the HO group presents an increased percentage of circulating T cells and a decreased percentage of B and natural killer (NK) cells, leading to the highest T/B-cell ratio in comparison with the other groups. Interestingly, while an increased percentage of activated CD4+HLA-DR+ T lymphocytes was observed in both AM and HO, only HO presented higher percentage of activated CD8+HLA-DR+ in combination with the highest CD18 surface expression. This was true for all cell populations analysed, including T lymphocytes, monocytes and neutrophils. Moreover, the HO group was distinguished by a dramatic decrease in the percentage of CD8+CD28+ lymphocytes. Taken together, these findings demonstrate a potent cellular immune activation response involving primarily CD8+ T cells that is concomitant with disease progression in HAM/TSP. We also show that an upregulation of CD18 expression, a hallmark for increased cell migratory potential, might play a critical role in the development/maintenance of HAM/TSP.

Preconditioning with hyperbaric oxygen and hyperoxia induces tolerance against spinal cord ischemia in rabbits.

The aim of this study was to determine if the ischemic tolerance could be induced in the spinal cord by pretreatment with hyperbaric oxygen (HBO) and what components of HBO (hyperoxia, hyperbaricity, and combination of these two) were critical in the induction of tolerance against ischemic injury. In experiment 1, 21 rabbits were randomly assigned to one of three groups (n = 7 each): animals in the control group received no HBO before spinal cord ischemia; animals in the HBO-1 and HBO-2 groups received HBO (2.5 atmosphere absolute [ATA], 100% O2) pretreatment 1 h/day for 3 and 5 days before ischemia, respectively. In experiment 2, 48 rabbits were randomly assigned to one of four groups (n = 12 each): the control group received no HBO (21% O2, 1 ATA, 1 h/day, 5 days) before spinal cord ischemia; the HB group received 1-h treatment in 21% O2 at 2.5 ATA each day for 5 days; the HO group received 1-h treatment in 100% oxygen at 1 ATA each day for 5 days; and the HBO group received HBO (2.5 ATA, 100% O2) treatment 1 h/day for 5 days. Twenty-four hours after the last treatment, spinal cord ischemia was induced by an infrarenal aorta clamping for 20 min. Forty-eight hours after reperfusion, hind-limb motor function and histopathology of the spinal cord were examined in a blinded fashion. In experiment 1, the neurologic outcome in the HBO-2 group was better than that of the control group (P = 0.004). The number of normal neurons in the anterior spinal cord in the HBO-2 group was more than that of the control group (P = 0.021). In experiment 2, the neurologic and histopathologic outcomes in the HBO group were better than that of the control group (P < 0.01). The histopathologic outcome in the HO group was better than that in the control group (P < 0.05). Serial exposure to high oxygen tension induced ischemic tolerance in spinal cord of rabbits. Simple hyperbaricity (2.5 ATA, 21% O2) did not induce ischemic tolerance.

Teratogenic Actions of Thermally-stressed Culinary Oils in Rats

Lipid oxidation products (LOPs), generated in culinary oils during episodes of thermal stressing can give rise to cellular damage. The aims of this study were to determine whether orally-administered, LOP-containing thermally-stressed safflower oil exerts teratogenic actions in rats, and whether this effect could be prevented by co-administration of f -tocopherol ( f -TOH). Safflower oil was heated for a period of 20 min according to standard frying practices and stored at m 20°C under N 2 . Four experimental groups of pregnant Wistar rats were employed; two received 0.30 ml of pre-heated oil (HO), one of which was also supplemented with 150 mg of f -TOH (HOE), and two served as controls, one treated with the non-heated oil (O) and the other without any treatment (C). The oil was administered daily by gavage from day 1 of pregnancy to day 11.5, when the animals were killed and the embryos examined. LOPs and f -TOH were determined both in the heated and non-heated oils. The percentage of embryo malformations and reabsorptions were determined in the above four experimental groups. Heating the oil substantially increased its concentration of LOPs and decreased its f -TOH content. The percentage of embryo malformations in the HO group was 21.73%, compared with 5.6 and 7% in the O and C groups, respectively. Supplementation of the pre-heated oil with f -TOH was found to decrease the percentage of malformations to 7%. The results obtained from these investigations indicate that LOPs detectable at millimolar levels in the heated cooking oils administered (e.g. saturated and f, g -unsaturated aldehydes, and/or their conjugated hydroperoxydiene precursors) exert potent teratogenic actions in experimental animals which are at least partially circumventable by co-administration of the chain-breaking antioxidant f -TOH. Plausible mechanisms for these processes and their health relevance to humans regarding diet and methods of frying/cooking are discussed.

Oxidized Frying Oil Up-Regulates Hepatic Acyl-CoA Oxidase and Cytochrome P450 4 A1 Genes in Rats and Activates PPARα

Oxidized LDL (oxLDL) and its component hydroxy fatty acids were shown to activate peroxisome proliferator-activating receptor alpha (PPARalpha) and gamma (PPARgamma). To test the hypothesis that lipid oxidation products in oxidized frying oil (OFO) can activate PPARalpha and up-regulate its target genes, a feeding experiment and a transactivation experiment were conducted. Based on a 2 x 2 factorial design, four groups of Sprague-Dawley male weanling rats were fed diets containing either high (20 g/100 g, HO and HF) or low (5 g/100 g, LO and LF) levels of oxidized frying soybean oil (HO and LO) or fresh soybean oil (HF and LF) for 6 wk. The OFO sample was prepared by frying wheat dough sheets in soybean oil at 205 +/- 5 degrees C for 24 h. OFO dose dependently and significantly increased (P < 0.05) mRNA of acyl-CoA oxidase (ACO) and cytochrome P(450) 4A1(CYP4A1) in liver of rats. Dietary OFO also dose dependently increased liver microsomal CYP4A protein (P < 0.05). The activity of hepatic ACO of the HO group was sixfold that of the HF group (P < 0.05). Plasma total lipids, liver triglycerides, cholesterol and total lipids were reduced in rats fed the LO and HO diets (P < 0.05). Through the ligand binding domain of PPARalpha, the hydrolyzed OFO enhanced the expression of alkaline phosphatase (ALP) reporter gene to a significantly greater extent (P < 0.05) than the hydrolyzed fresh soybean oil in a transactivation assay using a clone of CHO K1 cells stably expressing Gal4-PPARalpha chimeric receptor and UAS4-ALP reporter. The results support our hypothesis that dietary OFO, by activating PPARalpha, up-regulates the expression of PPARalpha downstream genes and alters lipid metabolism in rats.

Effects of hyperglycemia or hypoglycemia on brain cell membrane function and energy metabolism during the immediate reoxygenation–reperfusion period after acute transient global hypoxia–ischemia in the newborn piglet

This study was done to determine the effects of hyperglycemia or hypoglycemia on brain cell membrane function and energy metabolism during the immediate reoxygenation–reperfusion period after hypoxia–ischemia (HI). Forty-five newborn piglets were divided randomly into four experimental groups: normoxia control (NC, n=9); HI/reoxygenation–reperfusion (RR) control (HC, n=11); HI/RR hyperglycemia (HE, n=12); and HI/RR hypoglycemia (HO, n=13) group. Animals were subjected to transient HI for 30 min followed by 2 h of RR. Cerebral HI was induced by temporary but complete occlusion of bilateral common carotid arteries with surgical clips and simultaneous breathing with 8% oxygen. Glucose was unregulated in HC group, and controlled by modified glucose clamp technique immediately after HI in HE (350 mg/dl) and HO (50 mg/dl) groups. During HI, heart rate, base deficit, glucose and lactate level in the blood and cerebrospinal fluid increased, and arterial pH, oxygen saturation and blood pressure decreased significantly in HC, HE and HO groups. During RR, these abnormalities returned to normal values, but lactic acidosis persisted especially in HO group. Cerebral Na +,K +-ATPase activity decreased, and lipid peroxidation products increased significantly in HC group than in NC group, and these abnormalities were significantly aggravated in HE, but not in HO, group. Brain ATP and phosphocreatine levels in HE group were significantly reduced compared to the corresponding values in NC, HC and HO groups. In summary, hyperglycemia, but not hypoglycemia immediately after HI interfered with the recovery of brain cell membrane function and energy metabolism. These findings suggest that post-hypoxic–ischemic hyperglycemia is not beneficial and might even be harmful in neonatal hypoxic–ischemic encephalopathy.

Hostility-related differences in the associations between stress-induced physiological reactivity and lipid concentrations in young healthy women

We examined the relations of fasting lipid levels to stress-induced neuroendocrine and cardiovascular responses as a function of hostility in 36 healthy young women. Participants were women who scored above 17 (n = 23) or below 12 (n = 13) on the Cook-Medley Hostility (Ho) Inventory. Lipids were determined following an overnight fast. Individuals participated in a solvable anagram task, which evoked significant physiological responses in all participants. The Ho group by total serum cholesterol (TSC) and the Ho group by low-density lipoprotein (LDL) cholesterol interactions significantly predicted heart rate (HR) and norepinephrine (Ne) responses. For high Ho women, elevations in TSC and LDL cholesterol were associated with smaller HR responses and larger Ne responses. In contrast, for low Ho women, elevations in TSC and LDL cholesterol were associated with larger HR responses and smaller Ne responses. Results also indicated a significant Ho group by TSC to high density lipoprotein (HDL) cholesterol ratio interaction for cortisol. For high Ho women, larger cortisol responses were associated with a greater TSC to HDL cholesterol ratio. For low Ho women, larger cortisol responses were associated with a smaller TSC to HDL cholesterol ratio. Lastly, higher TSC and LDL cholesterol levels were significantly associated with larger epinephrine responses. The findings suggest that stress-induced physiological responses are differentially associated with fasting lipids as a function of hostility in healthy young women.

Exercise- and methylcholine-induced sweating responses in older and younger men: effect of heat acclimation and aerobic fitness.

The purpose of this investigation was to examine the effects of aging and aerobic fitness on exercise- and methylcholine-induced sweating responses during heat acclimation. Five younger [Y group-age: 23 +/- 1 (SEM) years; maximal oxygen consumption (VO2max): 47 +/- 3 ml.kg-1.min-1], four highly fit older (HO group- 63 +/- 3 years; 48 +/- 4 ml.kg-1.min-1) and five normally fit older men (NO group -67 +/- 3 years; 30 +/- 1 ml.kg-1.min-1) who were matched for height, body mass and percentage fat, were heat acclimated by daily cycle exercise (approximately 35% VO2max for 90 min) in a hot (43 degrees C, 30% RH) environment for 8 days. The heat acclimation regimen increased performance time, lowered final rectal temperature (Tre) and percentage maximal heart rate (%HRmax), improved thermal comfort and decreased sweat sodium concentration similarly in all groups. Although total body sweating rates (Msw) during acclimation were significantly greater in the Y and HO groups than in the NO group (P < 0.01) (because of the lower absolute workload in the NO group), the Msw did not change in all groups with the acclimation sessions. Neither were local sweating rates (msw) on chest, back, forearm and thigh changed in all groups by the acclimation. The HO group presented greater forearm msw (30-90 min) values and the Y group had greater back and thigh msw (early in exercise) values, compared to the other groups (P < 0.001). In a methylcholine injection test on days immediately before and after the acclimation, the order of sweat output per gland (SGO) on chest, back and thigh was Y > HO > NO, and on the forearm Y = HO > NO. No group differences were observed for activated sweat gland density at any site. The SGO at the respective sites increased in the post-acclimation test regardless of group (P < 0.01), but on the thigh the magnitude of the increase was lower in the NO (P < 0.02) and HO (P = 0.07) groups than in the Y group. These findings suggest that heat tolerance and the improvement with acclimation are little impaired not only in highly fit older but also normally fit older men, when the subjects exercised at the same relative exercise intensity. Furthermore, the changes induced by acclimation appear associated with an age-related decrease in VO2max. However methylcholine-activated SGO and the magnitude of improvement of SGO with acclimation are related not only to VO2max but also to aging, suggesting that sensitivity to cholinergic stimulation decreases with aging.

Impact of insulin and body mass index on metabolic and endocrine variables in polycystic ovary syndrome

To assess the differential impact of the insulin secretory pattern and obesity on the endocrinometabolic features of the polycystic ovary syndrome (PCOS), we studied 110 PCOS women. Patients underwent a gonadotropin-releasing hormone (GnRH) test, an oral glucose tolerance test (OGTT), and basal evaluation of hormonal and biochemical parameters. Basal androgens and lipids, basal and stimulated gonadotropins, insulin, and glucose levels were measured. Patients were classified into four groups according to the body mass index (BMI) and insulin secretion: normoinsulinemic-lean ([NL] n = 24), normoinsulinemic obese ([NO] n = 24), hyperinsulinemic lean ([HL] n = 17), hyperinsulinemic obese ([HO] n = 45). HL patients showed a higher luteinizing hormone (LH) area under curve (AUC) after GnRH stimulus compared with NL patients (HL v NL, 4,285 +/- 348 v 3,377 +/- 314 IU/L x 120 min, P < .05), whereas we failed to find a statistically significant difference in a similar comparison among obese subjects (HO v NO, 3,606 +/- 302 v 3,129 +/- 602 IU/L x 120 min). A trend toward increased plasma testosterone and decreased sex hormone-binding globulin (SHBG) was found in relation to hyperinsulinemia and obesity, thus resulting in a higher free androgen index (FAI) in groups HL and NO versus NL (HL, 5.54 +/- 0.51; NO, 5.64 +/- 0.49; NL, 4.13 +/- 0.33; P < .05 and P < .01, respectively). The presence of both exaggerated insulin secretion and obesity resulted in a synergistic additive effect on the FAI in the HO group (6.81 +/- 0.34). Concerning the lipoprotein lipid profile, the NL group showed lower plasma triglyceride levels compared with the other three groups, whereas no significant differences were found for nonesterified fatty acid (NEFA) concentrations. Higher low-density lipoprotein cholesterol (LDL-C) and very-low-density lipoprotein cholesterol (VLDL-C) and lower high-density lipoprotein cholesterol (HDL-C) levels were found in the obese groups compared with the lean counterparts, whereas the same parameters did not significantly differ in a comparison between normoinsulinemic and hyperinsulinemic groups. In conclusion, our data suggest an important role of hyperinsulinemia in the LH response to a GnRH stimulus and an independent and synergistic additive effect of obesity and hyperinsulinemia on the FAI in PCOS.

Anab InitioComputational Molecular Orbital Study of Radical, Protonated Radical (Radical Cation), and Carbocation Species That Have Been Proposed in Mechanisms for the Transfer Process in the Enzyme−Coenzyme B12-Catalyzed Dehydration of 1,2-Dihydroxyethane

The mechanism of action of the enzyme diol dehydrase has variously been suggested to involve a radical, a protonated radical (radical cation), or a carbocation in the apparent transfer of HO from one carbon atom to the other to give acetaldehyde and water. This adenosylcobalamin-requiring B12 enzyme catalyzes dehydration of 1,2-dihydroxyethane. Its active site is buried within a hydrophobic cavity. Each of the three possibilities are examined by ab initio molecular orbital calculations. Total molecular energies have been calculated with full geometry optimization at the MP2(FC)/6-31G* level and, in addition, single point energies using the MP2(FC)/6-311++G** basis set. Vibrational frequencies were also calculated. Transfer of an HO group within a HOCH−CH2OH⎤• radical (postulated to be formed by the initial reaction of the diol with the deoxyadenosyl radical via a bridge structure) was ruled out because the activation energy is much too high in relation to the observed rate constant for the enzyme reaction...