OBJECTIVE

To evaluate the scientific evidence on guggul for hyperlipidemia including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

METHODS

Electronic searches were conducted in nine databases, 20 additional journals (not indexed in common databases), and bibliographies from 50 selected secondary references. No restrictions were placed on language or quality of publications. All literature collected pertained to efficacy in humans, dosing, precautions, adverse effects, use in pregnancy/lactation, interactions, alteration of laboratory assays, and mechanism of action. Standardized inclusion/exclusion criteria were utilized for selection.

RESULTS

Before 2003, most scientific evidence suggested that guggulipid elicits significant reductions in serum total cholesterol, low-density lipoprotein (LDL), and triglycerides, as well as elevations in high-density lipoprotein (HDL) [Kotiyal JP, Bisht DB, Singh DS. Double blind cross-over trial of gum guggulu (Commiphora mukul) Fraction A in hypercholesterolemia. J Res Indian Med Yoga Hom 1979;14(2):11-6; Kotiyal JP, Singh DS, Bisht DB. Gum guggulu (Commiphora mukul) fraction 'A' in obesity-a double-blind clinical trial. J Res Ayur Siddha 1985;6(1, 3, 4):20-35; Gaur SP, Garg RK, Kar AM, et al. Gugulipid, a new hypolipidaemic agent, in patients of acute ischaemic stroke: effect on clinical outcome, platelet function and serum lipids. Asia Pacif J Pharm 1997;12:65-9; Urizar NL, Liverman AB, Dodds DT, et al. A natural product that lowers cholesterol as an antagonist ligand for the FXR. Science 3 May 2002 [Science Express Reports]; Nityanand S, Srivastava JS, Asthana OP. Clinical trials with gugulipid. A new hypolipidaemic agent. J Assoc Physicians India 1989;37(5):323-8; Kuppurajan K, Rajagopalan SS, Rao TK, et al. Effect of guggulu (Commiphora mukul-Engl.) on serum lipids in obese, hypercholesterolemic and hyperlipemic cases. J Assoc Physicians India 1978;26(5):367-73; Gopal K, Saran RK, Nityanand S, et al. Clinical trial of ethyl acetate extract of gum gugulu (gugulipid) in primary hyperlipidemia. J Assoc Physicians India 1986;34(4):249-51; Agarwal RC, Singh SP, Saran RK, et al. Clinical trial of gugulipid-a new hypolipidemic agent of plant origin in primary hyperlipidemia. Indian J Med Res 1986;84:626-34; Verma SK, Bordia A. Effect of Commiphora mukul (gum guggulu) in patients of hyperlipidemia with special reference to HDL-cholesterol. Indian J Med Res 1988;87:356-60; Singh RB, Niaz MA, Ghosh S. Hypolipidemic and antioxidant effects of Commiphora mukul as an adjunct to dietary therapy in patients with hypercholesterolemia. Cardiovasc Drugs Ther 1994;8(4):659-64; Ghorai M, Mandal SC, Pal M, et al. A comparative study on hypocholesterolaemic effect of allicin, whole germinated seeds of bengal gram and guggulipid of gum gugglu. Phytother Res 2000;14(3):200-02]. However, most published studies were small and methodologically flawed. In August 2003, a well-designed trial reported small significant increases in serum LDL levels associated with the use of guggul compared to placebo [Szapary PO, Wolfe ML, Bloedon LT, et al. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial. JAMA 2003;290(6):765-72]. No significant changes in total cholesterol, high-density lipoprotein (HDL), or triglycerides were measured. These results are consistent with two prior published case reports [Das Gupta R. Gugulipid: pro-lipaemic effect. J Assoc Physicians India 1990;38(12):346].

CONCLUSIONS

The effects of guggulipid in patients with high cholesterol are not clear, with some studies finding cholesterol-lowering effects, and other research suggesting no benefits. At this time, there is not enough scientific evidence to support the use of guggul for any medical condition. Guggul may cause stomach discomfort or allergic rash as well as other serious side effects and interactions. It should be avoided in pregnant or breast-feeding women and in children. Safety of use beyond 4 months has not been well studied.

Bone metastases are a frequent complication of cancer. With advances in effective systemic treatment and supportive care, the survival of patients with bone metastases has improved substantially. Treatment options for bone metastases have been expanding, as reflected in the latest clinical trials testing newer generations of bisphosphonates and increased use of orthopedic surgery. There is a great need to monitor not only the benefits but also the side effects of these treatments. Any interventions should aim primarily at improving the quality of life (QoL) in this group of terminal patients. The use of validated bone metastases-specific QoL instruments should be promoted for use in both daily practice and clinical trials. In response to the need for a comprehensive bone metastases-specific QoL instrument, which has been lacking until now, we have developed the European Organization for Research and Treatment of Cancer (EORTC) QoL Group Bone Metastases Module (QLQ-BM22) according to the module development guidelines of the EORTC Quality of Life Group (QLG). As bone metastases patients are palliative and often demonstrate rapid deterioration, we will conduct Phase IV testing of the EORTC QLQ-BM22 alongside the EORTC QLQ-C15-PAL palliative core questionnaire to ease patient burden when completing the study assessments. The international validation of the Bone Metastases Module will facilitate measurement of important QoL issues in palliative care trials. Healthcare professionals will be able to reliably follow their patients' QoL, help patients in choosing treatments and assess the cost-effectiveness of the treatments. Bone metastases clinical trial QoL outcomes will be compared across trials through the utilization of a consistent and valid module questionnaire.

Transcription of genes encoding L-phenylalanine ammonia-lyase (PAL), the first enzyme of the phenylpropanoid pathway, and caffeic acid 3-O-methyltransferase (COMT) and caffeoyl CoA 3-O-methyltransferase (CCOMT), enzymes involved in the synthesis of lignin and wall-esterified phenolic compounds, was strongly activated in elicitor-treated cell-suspension cultures of alfalfa (Medicago sativa L.). However, consequent changes in the extractable activities of COMT and CCOMT were small to nonexistent compared with a 15- to 16-fold increase in PAL activity. Only low levels of COMT and CCOMT transcripts were reflected in the total and polysomal RNA fractions compared with PAL transcripts. Elicited cell cultures did not accumulate lignin or the products of COMT and CCOMT in the soluble and wall-esterified phenolic fractions. In one alfalfa cell line in which elicitation resulted in very high PAL activity and increased deposition of methoxyl groups in the insoluble wall fraction, there was still no change in COMT and CCOMT activities. Overall, these results indicate that the initial gene transcription events in elicited cells may be less selective than the subsequent metabolic changes, highlighting the importance of posttranscriptional events in the control of phenylpropanoid biosynthesis.

Methyl jasmonate inhibited the harpin-induced defense responses such as cell death, H2O2 generation and gene expression encoding phenylalanine ammonia-lyase in tobacco suspension cultured BY-2 cells. These results suggest that MeJA may act as an endogenous suppressor for plant defense response including hypersensitive reaction.

Effector genes of some plant-pathogenic bacteria, including some members of the avrBs3/pthA effector gene family from Xanthomonas spp., confer not only genotype-specific disease resistance but also pathogen aggressiveness or virulence. In addition, some effector gene products suppress induction of a nonspecific (or general) hypersensitive response (HR). To determine whether the Xanthomonas avrBs3/pthA gene family members apl1, avrXa7, or avrXa10 also confer suppressor activity, we introduced constructs with each effector gene into Pseudomonas fluorescens 55 that expressed the entire hrp cluster from P. syringae pv. syringae in cosmid pHIR11. When inoculated to tobacco 'Bright Yellow', P fluorescens (pHIR11) induces the HR and expression of four tobacco defense response genes: HIN1, RbohB, PAL, and PR1. When P. fluorescens double transformants that contained pHIR11 and constructs with apl1, avrXa7, or avrXa10 were infiltrated into tobacco, the HR and expression of three defense response genes, RbohB, PAL, and PR1, were suppressed. The suppression of the HR and defense gene expression was more efficient in the transformants with the apl1 and avrXa7 than the transformant with avrXa10. Although expression of other defense genes was suppressed by the double transformants, HIN1 expression was the same level as was observed after infiltration with P. fluorescens (pHIR11), suggesting that HIN1 may not be involved directly in HR. Taken together, our data suggest that avrXa7, avrXa10, and apl1, when delivered to plant cells by the P. syringae pv. syringae hrp secretion system, can suppress nonhost HR and associated phenotypes.

The suppressive ability of several strains of cyclic lipopeptide-producing Bacillus rhizobacteria to grey leaf spot disease caused by Magnaporthe oryzae has been documented previously; however, the underlying mechanism(s) involved in the induced systemic resistance (ISR) activity in perennial ryegrass (Lolium perenne L.) remains unknown. Root-drench application of solid-phase extraction (SPE)-enriched surfactin and live cells of mutant Bacillus amyloliquefaciens strain FZB42-AK3 (produces surfactin, but not bacillomycin D and fengycin) significantly reduced disease incidence and severity on perennial ryegrass. The application of the treatments revealed a pronounced multilayered ISR defence response activation via timely and enhanced accumulation of hydrogen peroxide (H2O2), elevated cell wall/apoplastic peroxidase activity, and deposition of callose and phenolic/polyphenolic compounds underneath the fungal appressoria in naïve leaves, which was significantly more intense in treated plants than in mock-treated controls. Moreover, a hypersensitive response (HR)-type reaction and enhanced expression of LpPrx (Prx, peroxidase), LpOXO4 (OXO, oxalate oxidase), LpPAL (PAL, phenylalanine ammonia lyase), LpLOXa (LOX, lipoxygenase), LpTHb (putative defensin) and LpDEFa (DEFa, putative defensin) in perennial ryegrass were associated with SPE-enriched surfactin and live AK3 cell treatments, acting as a second layer of defence when pre-invasive defence responses failed. The results indicate that ISR activity following surfactin perception may sensitize H2O2 -mediated defence responses, thereby providing perennial ryegrass with enhanced protection against M. oryzae.

Salvia miltiorrhiza Bunge is a well-known material of traditional Chinese medicine. Hydrophilic phenolic acids, such as rosmarinic acid and salvianolic acid B, are a group of pharmaceutically important compounds in S. miltiorrhiza. The biosynthesis of rosmarinic acid requires the coordination of the phenylpropanoid pathway and the tyrosine-derived pathway. Phenylalanine ammonia-lyase (PAL) is the first key enzyme of the phenylpropanoid pathway. Systematic analysis of the SmPAL gene family has not been carried out. We report here the identification of three SmPALs through searching the recently obtained working draft of the S. miltiorrhiza genome and full-length cDNA cloning. Bioinformatic and phylogenetic analyses showed that SmPALPALPALs, whereas SmPALPAL promoters, whereas the others were not. SmPALPALPALPALPALPALs were induced in roots treated with PEG and MeJA, but the time and degree of responses were different, suggesting the complexity of SmPAL-associated metabolic network in S. miltiorrhiza. This is the first comprehensive study dedicated to SmPAL gene family characterization. The results provide a basis for elucidating the role of SmPAL genes in the biosynthesis of bioactive compounds.

Physiological responses of Matricaria chamomilla plants exposed to cadmium (Cd) and copper (Cu) excess (3, 60, and 120 microM for 7 days) with special emphasis on phenolic metabolism were studied. Cu at 120 microM reduced chamomile growth, especially in the roots where it was more abundant than Cd. Notwithstanding the low leaf Cu amount (37.5 microg g(-1) DW) in comparison with Cd (237.8 microg g(-1) DW) at 120 microM, it caused reduction of biomass accumulation, F(v)/F(m) ratio and soluble proteins. In combination with high accumulation of phenolics, strong reduction of proteins and high GPX activity in the roots, this supports severe redox Cu properties. In terms of leaf phenylalanine ammonia-lyase (PAL) activity, it seems that Cd had a stimulatory effect during the course of the experiment, whereas Cu was found to stimulate it after 7-day exposure. The opposite trend was visible in the roots, where Cd had a stimulatory effect at high doses but Cu mainly at the highest dose. This supports the assumption of different PAL time dynamics under Cd and Cu excess. A dose of 60 and 120 microM Cu led to 2- and 3-times higher root lignin accumulation while the same Cd doses increased it by 33 and 68%, respectively. A Cu dose of 120 microM can be considered as limiting for chamomile growth under conditions of present research, while resistance to high Cd doses was confirmed. However, PAL and phenolics seemed to play an important role in detoxification of Cd- and Cu-induced oxidative stress.

Several abiotic stresses, including ethylene, methyl jasmonate, temperature, light, and wounding, were tested for their ability to induce accumulation of phenolic compounds and antioxidant capacity in purple-flesh potatoes (cv. All Blue). Results indicated that temperature, ethylene, methyl jasmonate, and light treatments did not significantly affect the accumulation of phenolic compounds compared to control samples. Only tubers with low initial anthocyanin levels treated with methyl jasmonate showed approximately 60% anthocyanin accumulation. Wounding induced the accumulation of phenolics compounds and an increase of PAL-activity in sliced tissue compared to the control. Total phenolics increased approximately 60% with a parallel 85% increase in antioxidant capacity. These results show that selection of appropriate abiotic stresses can enhance the nutritional and functional value of potatoes.

BACKGROUND

Western women frequently exhibit excessive gestational weight gain (GWG). The effects of maternal physical activity level (PAL) and body mass index (BMI) on the timing of GWG are insufficiently known.

OBJECTIVE

To assess the impact of pre-pregnancy PAL and BMI on GWG during the second and third trimester and on birth weight.

METHODS

Body weight was measured in 223 healthy Swedish women in gestational weeks 12, 25 and 33, and GWG during the second (weeks 12-25) and third trimesters (weeks 25-33) was determined (kg/week). PAL was assessed using a questionnaire. Birth weights were obtained from birth records. The results were evaluated by the fitting of linear statistical models.

RESULTS

Some 50 and 80% of the women exhibited excessive GWG during the second and third trimesters, respectively. Women with a high pre-pregnancy PAL gained 0.10 kg/week (p=0.04) less weight during the third trimester than women with a medium PAL. A 5 kg/m(2) higher BMI was associated with a 0.06 kg/week lower GWG in the second trimester (p=0.005), but with a 0.05 higher GWG in the third trimester (p=0.03). Maternal BMI (p=0.014) and total GWG (p=0.05) correlated with birth weight.

CONCLUSIONS

High BMI and low pre-pregnancy PAL were associated with excessive GWG. BMI and GWG, but not pre-pregnancy PAL, were linked to birth weight. However, together with smoking, parity, education and age, pre-pregnancy PAL and BMI explained only 4% of the variation in GWG. Thus, identification of other factors that could explain excessive GWG is an important area of future research.

Fragile X syndrome is caused by silencing of FMR-1 gene due to unusual expansion of CGG repeats (>200 repeats) and their hypermethylation in 5'-UTR. As a consequence, the expression of the RNA binding protein FMRP is stopped. Absence of this protein leads to several morphological and neurological symptoms. The symptoms of the syndrome in males are different than that in the females. We have previously reported that the Fmr1 gene is down regulated in males as a function of age. In the present communication, we have investigated expression of Fmr-1 mRNA, FMRP and analysis of interaction of trans-acting factors with E- and GC boxes in Fmr-1 promoter in female mouse brain as a function of age. Our Northern and Western blots data reveal that the level of Fmr-1 transcript decreases in adult as compared to young mouse but significantly increases in old age and that of FMRP decreases in brain of female old mouse as compared to young and adult age. The immunohistochemical analysis supported the results obtained from Western blot studies. Our EMSA data reveal that the intensity of USF1/USF2-E Box complex gradually increases during aging having significantly highest intensity in old age mouse whereas the intensity of alpha-Pal/Nrf1- GC-Box complex gradually decreases as a function of age. The increased intensity of the complex in old age mouse is correlated to higher level of Fmr-1 transcript in old age. The elevated level of Fmr-1 transcript in old mouse brain may be attributed to USF1/USF2 dependent increased transcription of Fmr-1 gene in old age and decrease in FMRP to altered translation of the transcript or high turn over of FMRP during aging. The present finding indicates age and sex as factors affecting the expression of Fmr-1 gene in mouse brain.

OBJECTIVE

Mechanical analyses of idealized crown-cement-tooth systems through finite element analysis (FEA) has provided valuable insight concerning design parameters and materials that favor lower stress patterns. However, little information regarding variation of basic preparation guidelines in stress distribution has been available. The primary objective of this study was to evaluate maximum principal stresses on a molar crown veneer plus core system natural tooth configuration preparation with variations in the ratio of proximal axial length (PAL) to buccal axial length (BAL) as well as loading condition and position.

METHODS

Three-dimensional models comprising a crown veneer (porcelain), crown core (zirconia), cement layer, and tooth preparation (4.2 mm BAL with PAL reductions of 0.8 mm, 1.0 mm, and 1.2 mm) yielding BAL:PAL ratios of 1.23, 1.31, and 1.4 were designed by computer software (Pro/Engineering). The models were imported into an FEA software (Pro/Mechanica), with all degrees of freedom constrained at the root surface of the tooth preparation. Each tooth preparation crown configuration was evaluated under a vertical (axial) 200 N load, and under a combined vertical 200 N and horizontal (buccally) 100 N load applied at different positions from the central fossa to the cusp tip. Maximum principal stress (MPS) was determined for the crown core for each crown BAL:PAL ratio, loading condition, and position.

RESULTS

Under both vertical and combined loading conditions, the highest MPSs were located at the occlusal region and in the occlusogingival region of the ceramic core. MPS values increased in the proximal region as the BAL:PAL ratio increased. Combined loading resulted in a general increase in MPS compared to vertical loading.

CONCLUSIONS

Increasing the BAL:PAL ratio (reducing the proximal axial length of the preparation) acted as a stress concentrator at regions near the crown margins, suggesting this area may be vulnerable to damage from fit adjustment as well as during function. Such increases in stress concentration should be considered in clinical scenarios, especially when inherent flaws are present in the material, since extensive high-magnitude tensile stress fields have been noted under all loading conditions.

After fertilization in C. elegans, activities encoded by the maternally expressed par genes appear to establish cellular and embryonic polarity. Loss-of-function mutations in the par genes disrupt anterior-posterior (a-p) asymmetries in early embryos and result in highly abnormal patterns of cell fate. Little is known about how the early asymmetry defects are related to the cell fate patterning defects in par mutant embryos, or about how the par gene products affect the localization and activities of developmental regulators known to specify the cell fate patterns made by individual blastomeres. Examples of such regulators of blastomere identity include the maternal proteins MEX-3 and GLP-1, expressed at high levels anteriorly, and SKN-1 and PAL-1, expressed at high levels posteriorly in early embryos. To better define par gene functions, we examined the expression patterns of MEX-3, PAL-1 and SKN-1, and we analyzed mex-3, pal-1, skn-1 and glp-1 activities in par mutant embryos. We have found that mutational inactivation of each par gene results in a unique phenotype, but in no case do we observe a complete loss of a-p asymmetry. We conclude that no one par gene is required for all a-p asymmetry and we suggest that, in some cases, the par genes act independently of each other to control cell fate patterning and polarity. Finally, we discuss the implications of our findings for understanding how the initial establishment of polarity in the zygote by the par gene products leads to the proper localization of more specifically acting regulators of blastomere identity.

The bacterial flagellar stator proteins, MotA and MotB, form a complex and are thought to be anchored to the peptidoglycan by the C-terminal conserved peptidoglycan-binding (PGB) motif of MotB. To clarify the role of the C-terminal region, we performed systematic cysteine mutagenesis and constructed a chimeric MotB protein which was replaced with the peptidoglycan-associated lipoprotein Pal. Although this chimera could not restore motility to a motB strain, we were able to isolate two motile revertants. One was F172V in the Pal region and the other was P159L in the MotB region. Furthermore, we attempted to map the MotB Cys mutations in the crystal structure of Escherichia coli Pal. We found that the MotB mutations that affected motility nearly overlapped with the predicted PG-binding residues of Pal. Our results indicate that, although the functions of MotB and Pal are very different, the PGB region of Pal is interchangeable with the PGB region of MotB.

We have previously shown that CdSe/ZnS core/shell luminescent semiconductor nanocrystals or QDs (quantum dots) coated with PEG [poly(ethylene glycol)]-appended DHLA (dihydrolipoic acid) can bind AcWG(Pal)VKIKKP(9)GGH(6) (Palm1) through the histidine residues. The coating on the QD provides colloidal stability and this peptide complex uniquely allows the QDs to be taken up by cultured cells and readily exit the endosome into the soma. We now show that use of a polyampholyte coating [in which the neutral PEG is replaced by the negatively heterocharged CL4 (compact ligand)], results in the specific targeting of the palmitoylated peptide to neurons in mature rat hippocampal slice cultures. There was no noticeable uptake by astrocytes, oligodendrocytes or microglia (identified by immunocytochemistry), demonstrating neuronal specificity to the overall negatively charged CL4 coating. In addition, EM (electron microscopy) images confirm the endosomal egress ability of the Palm1 peptide by showing a much more disperse cytosolic distribution of the CL4 QDs conjugated to Palm1 compared with CL4 QDs alone. This suggests a novel and robust way of delivering neurotherapeutics to neurons.

OBJECTIVE

To validate questionnaire-based physical activity level (PAL) against accelerometry and a 24 h physical activity diary (24 h AD) as reference methods (Protocol 2), after validating these reference methods against the heart rate-oxygen consumption (HRVO2) method (Protocol 1).

METHODS

Cross-sectional study.

METHODS

Two villages in Andhra Pradesh state and Bangalore city, South India.

METHODS

Ninety-four participants (fifty males, forty-four females) for Protocol 2; thirteen males for Protocol 1.

RESULTS

In Protocol 2, mean PAL derived from the questionnaire (1.72 (sd 0.20)) was comparable to that from the 24 h AD (1.78 (sd 0.20)) but significantly higher than the mean PAL derived from accelerometry (1.36 (sd 0.20); P < 0.001). Mean bias of PAL from the questionnaire was larger against the accelerometer (0.36) than against the 24 h AD (-0.06), but with large limits of agreement against both. Correlations of PAL from the questionnaire with that of the accelerometer (r = 0.28; P = 0.01) and the 24 h AD (r = 0.30; P = 0.006) were modest. In Protocol 1, mean PAL from the 24 h AD (1.65 (sd 0.18)) was comparable, while that from the accelerometer (1.51 (sd 0.23)) was significantly lower (P < 0.001), than mean PAL obtained from the HRVO2 method (1.69 (sd 0.21)).

CONCLUSIONS

The questionnaire showed acceptable validity with the reference methods in a group with a wide range of physical activity levels. The accelerometer underestimated PAL in comparison with the HRVO2 method.

The elimination of ammonia from alpha-amino acids is a chemically difficult process. While the non-acidic beta-proton has to be abstracted, the much more acidic ammonium protons must remain untouched to maintain the leaving group ability of this positively charged group. Histidine and phenylalanine ammonia-lyases (HAL and PAL) possess a catalytically essential electrophilic group which has been believed to be dehydroalanine for 30 years. Recently, the X-ray structure of HAL has been solved. The electron density was not consistent with dehydroalanine but showed the presence of methylidene imidazolone (MIO) instead. The high electrophilicity of this prosthetic group as well as the geometry at the active site support a previously proposed mechanism involving a Friedel-Crafts-type attack at the aromatic ring of the substrate. Further biochemical evidence for this unprecedented electrophile-assisted ammonia elimination is also presented. Although no X-ray structure of PAL has been published as yet, spectrophotometrical evidence for the presence of MIO has been provided. Finally, a chemical model for the PAL reaction is described.

Palmitic acid (Pal) is known to promote apoptosis (Sparagna G et al (2000) Am J Physiol Heart Circ Physiol 279: H2124-H2132) and its amount in blood and mitochondria increases under some pathological conditions. Yet, the mechanism of the proapoptotic action of Pal has not been elucidated. We present evidence for the involvement of the mitochondrial cyclosporin A-insensitive pore induced by Pal/Ca(2+) complexes in the apoptotic process. Opening of this pore led to a fall of the mitochondrial membrane potential and the release of the proapoptotic signal cytochrome c. The addition of cytochrome c prevented these effects and recovered membrane potential, which is in contrast to the cyclosporin A-sensitive mitochondrial permeability transition pore. Oleic and linoleic acids prevented the Pal/Ca(2+)-induced pore opening in the intact mitochondria, this directly and significantly correlating with the effect of these fatty acids on Pal-induced apoptosis in cells (Hardy S et al (2003) J Biol Chem 278: 31861-31870). The specific probe for cardiolipin, 10-N-nonyl acridine orange, inhibited formation of this pore.

Many neuropeptide transmitters require the presence of a carboxy-terminal alpha-amide group for biological activity. Amidation requires conversion of a glycine-extended peptide intermediate into a C-terminally amidated product. This post-translational modification depends on the sequential action of two enzymes (peptidylglycine alpha-hydroxylating monooxygenase or PHM, and peptidyl-alpha-hydroxyglycine alpha-amidating lyase or PAL) that in most eukaryotes are expressed as separate domains of a single protein (peptidylglycine alpha-amidating monooxygenase or PAM). We identified a cDNA encoding PHM in the human parasite Schistosoma mansoni. Transient expression of schistosome PHM (smPHM) revealed functional properties that are different from other PHM proteins; smPHM displays a lower pH-optimum and, when expressed in mammalian cells, is heavily N-glycosylated. In adult worms, PHM is found in the trans-Golgi network and secretory vesicles of both central and peripheral nerves. The widespread occurrence of PHM in the nervous system confirms the important role of amidated neuropeptides in these parasitic flatworms. The differences between schistosome and mammalian PHM suggest that it could be a target for new chemotherapeutics.

Upper motor neuron (UMN) dysfunction in Amyotrophic Lateral Sclerosis (ALS) is not easy to identify clinically: Diffusion Tensor Imaging (DTI) and single-voxel Magnetic Resonance Spectroscopy (H-MRS) can identify markers of UMN involvement. The aim of this study was to correlate brain DTI and MRS data with clinical parameters in ALS patients (PALS). We studied 32 PALS using Magnetic Resonance Imaging. The subjects were subdivided into definite/probable (D/P) and possible/suspected (P/S). DTI indices included Fractional Anisotropy (FA) and averaged Apparent Diffusion Coefficient (avADC). Anatomical areas were sampled by positioning regions of interest along corticospinal tracts, from the precentral cortex to the bulb. H-MRS voxels were localized bilaterally in precentral regions. D/P-PALS showed significantly lower FA values than healthy controls in almost all regions, whereas P/S-PALS FA values were significantly lower only in the left precentral gray matter (GM), right precentral white matter (WM), cerebral peduncles (CP), left hemipons, and left bulbar pyramid (BP). Significantly higher avADC values were observed in the D/P-PALS right precentral GM, precentral WM, right semioval center-posterior limb of the internal capsule (SC-PLIC), and left CP; and in the precentral WM, right SC-PLIC, left CP, and right hemipons of P/S-PALS. With increasing disability, only D/P-PALS showed significantly reduced FA values in the left precentral WM and hemipons, and increased avADC values in the precentral WM. Significantly lower N-acetylaspartate (NAA)/creatine-phosphocreatine complex (Cr) and higher choline (Cho)/Cr and myoinositol (mI)/Cr ratios were found in D/P-PALS, while only higher Cho/Cr and mI/Cr ratios were found in P/S-PALS. Our data highlight the usefulness of DTI and H-MRS in assessing UMN involvement. Given FA sensitivity and specificity, despite the small number of PALS, our findings support its use as a diagnostic marker in D/P-PALS.

Antibody-forming (plasma) cells and memory B cells are both generated during a humoral immune response in the spleen. Antibody-forming cells develop in the outer parts of the periarteriolar lymphocyte sheaths (PALS) while memory B cells develop in the lymphoid follicles. As soon as the first antibodies appear in the circulation, immune complexes are formed, the bulk of which are ingested by cells of the mononuclear phagocyte system. A small proportion, however, is immobilized on the processes of follicular dendritic cells (FDCs). These immune complexes are thought to play a key role in the generation of memory B cells in the follicles. In this article Nico van Rooijen postulates that, in the continuing presence of soluble antigen, the newly generated memory B cells in the follicles may continue to differentiate into antibody-forming cells. Experimentally such conditions are fulfilled when adjuvants that slowly release antigen are used and when antigens used for immunization can replicate in the body. The postulated synergistic action of immobilized immune complexes and soluble antigen in the follicles may represent an efficient mechanism for the rapid production of large numbers of plasma cells.

We assessed the ability of the Polar activity recorder (AR) to measure energy expenditure (EE) during military training. Twenty-four voluntary male conscripts participated in the study and wore an AR on the non-dominant wrist 24 h a day for 7 d. The AR analyzed and stored the frequency of hand movements (f_hand) into memory at 1 min intervals. The relationship between f_hand and EE was studied over a 7 d period of military training using the doubly labeled water (DLW) technique. In addition, the relationship between f_hand and EE was analyzed during walking and running on a treadmill with an indirect calorimeter (IC), and f_hand was measured during a supervised 45 min field march test where the conscripts carried combat gear. EE was expressed as physical activity level (PAL), total energy expenditure (TEE), and activity-induced energy expenditure adjusted for body mass (AEE/BM). Over the 7 d period, f_hand alone explained 46% of inter-individual variation in PAL(DLW). After inclusion of body height and mass in the model used to predict PAL(DLW) from f_hand, a very high positive correlation and a low standard error of estimate (SEE) were observed between the AR and DLW techniques: for TEE r = 0.86 (p < 0.001), the SEE was 6.3%, and for AEE/BM r = 0.84 (p < 0.001), the SEE was 12.8%. In the treadmill exercise, f_hand correlated highly with PAL(IC) (r = 0.97 ± 0.02). In the 45 min field march test, the AR measured similar f_hand as on the treadmill at the same speed. In conclusion, the wrist-worn AR can be regarded as a reliable and valid method for assessing EE during intensive training.

The aim of the present study was to compare epidemiological data of periodontal disease obtained from a sample of adults by means of different, commonly employed, partial and full-mouth index systems, in order to explore the amount of discrepancy attributed to the methodology per se. 169 dentate subjects, aged 25-64 years, were subjected to a clinical examination, including circumferential probing assessments of pocket depth (PPD) and attachment level (PAL) at all teeth present. The individual mean % of tooth sites with PPD of>> or = 6 mm and the % of subjects exhibiting at least one such deep pocket were calculated based on (i) full-mouth data, (ii) data derived from the buccal and mesial surfaces from 1 randomly selected upper and 1 lower quadrant, (iii) probing assessments at the 6 "Ramfjord teeth", (iv) the full-mouth community periodontal index for treatment needs (CPITN), and (v) the partial CPITN based on 10 index teeth. The PAL data were analyzed by means of 3 versions of the extent and severity index, 1 generated by full-mouth assessments and 2 by partial assessments based on 28 and 10 tooth sites, respectively. In the entire sample, the individual mean % of sites with PPD of>> or = 6 mm generated by the different systems ranged between 5.0 and 4.2 sites/subject. By full-mouth CPITN scorings, an average of 1.0 score-4 sextants/subject was recorded, while the partial CPITN generated a corresponding value of 0.8 score-4 sextants/subject.(ABSTRACT TRUNCATED AT 250 WORDS)