Electron beam ion sources for use in second generation synchrotrons for medical particle therapy.

Cyclotrons and first generation synchrotrons are the commonly applied accelerators in medical particle therapy nowadays. Next generation accelerators such as Rapid Cycling Medical Synchrotrons (RCMS), direct drive accelerators, or dielectric wall accelerators have the potential to improve the existing accelerator techniques in this field. Innovative accelerator concepts for medical particle therapy can benefit from ion sources which meet their special requirements. In the present paper we report on measurements with a superconducting Electron Beam Ion Source, the Dresden EBIS-SC, under the aspect of application in combination with RCMS as a well proven technology. The measurements indicate that this ion source can offer significant advantages for medical particle therapy. We show that a superconducting EBIS can deliver ion pulses of medically relevant ions such as protons, C(4 +) and C(6 +) ions with intensities and frequencies required for RCMS [S. Peggs and T. Satogata, "A survey of Hadron therapy accelerator technology," in Proceedings of PAC07, BNL-79826- 2008-CP, Albuquerque, New Mexico, USA, 2007; A. Garonna, U. Amaldi et al., "Cyclinac medical accelerators using pulsed C(6 +)/H2(+) ion sources," in Proceedings of EBIST 2010, Stockholm, Sweden, July 2010]. Ion extraction spectra as well as individual ion pulses have been measured. For example, we report on the generation of proton pulses with up to 3 × 10(9) protons per pulse and with frequencies of up to 1000 Hz at electron beam currents of 600 mA.

Production of low-Z ions in the Dresden superconducting electron ion beam source for medical particle therapy.

We report on experiments with a new superconducting electron beam ion source (EBIS-SC), the Dresden EBIS-SC, with the objective to meet the main requirements for their application in particle-therapy facilities. Synchrotrons as well as innovative accelerator concepts, such as high-gradient linacs which are driven by a large-current cyclotron (CYCLINACS) and direct drive RF linear accelerators may benefit from the advantages of EBISs in regard to their functional principle. First experimental studies of the production of low-Z ions such as H(+), H(2)(+), H(3)(+), C(4+), and C(6+) are presented. Particular attention is paid to the ion output, i.e., the number of ions per pulse and per second, respectively. Important beam parameters in this context are, among others, ion pulse shaping, pulse repetition rates, beam emittance, and ion energy spread.

Optical control of coherent interactions between electron spins in InGaAs quantum dots.

Coherent interactions between spins in quantum dots are a key requirement for quantum gates. We have performed pump-probe experiments in which pulsed lasers emitting at different photon energies manipulate two distinct subsets of electron spins within an inhomogeneous InGaAs quantum dot ensemble. The spin dynamics are monitored through their precession about an external magnetic field. These measurements demonstrate spin precession phase shifts and modulations of the magnitude of one subset of oriented spins after optical orientation of the second subset. The observations are consistent with results from a model using a Heisenberg-like interaction with µeV strength.

Short time ion pulse extraction from the Dresden electron beam ion trap.

We present measurements of the extraction of short time pulses of highly charged ions (4 keV, Ar(16+)) from the Dresden electron beam ion trap. Thereby the dependence of the extractable ionic charge on the extraction regime was investigated. The ion extraction time was varied between 20 ns and 1 micros. Furthermore the production of carbon ions and the influence of the extraction regime on the pulse widths was investigated to obtain information about the suitability of the Dresden EBIS-A in synchrotron based particle therapy facilities.

A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation.

BACKGROUND: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder characterized by progressive spastic paraparesis of the lower limbs. OBJECTIVE: To identify the genotype and characterize the phenotype in a family with a novel form of complicated autosomal recessive hereditary spastic paraparesis (ARHSP). METHODS: Six subjects of a Turkish family were examined by clinical evaluation, detailed neuropsychological testing, neurophysiologic studies, MRI, diffusion tensor imaging (DTI), and mutation analysis of SPG7 gene. RESULTS: Three individuals were affected by a juvenile-onset form of complicated ARHSP due to the missense mutation c.2075G>C in exon 15 of the SPG7 gene in the homozygous state, substituting serine with threonine at codon 692. As additional clinical features, cerebellar syndrome, supranuclear palsy, and cognitive impairment, particularly disturbance of attention and executive functions, were found. MRI showed cerebellar atrophy and mild frontal cerebral atrophy. DTI revealed bilateral disturbance of white matter integrity in corticospinal tracts, frontal lobes, and the midbrain. CONCLUSIONS: The new SPG7 gene mutation leads to a novel complicated autosomal recessive hereditary spastic paraparesis phenotype that widens the spectrum of different brain systems that are optionally affected in hereditary spastic paraplegia (HSP). In this novel phenotype, spastic paraparesis is related to cerebral damage of corticospinal tracts. Impairment of attention and executive functions is due to white matter loss in frontal lobes. Furthermore, supranuclear palsy is caused by white matter damage in the midbrain. This multisystem affection, which was detected by the use of diffusion tensor imaging, may reflect a mitochondrial dysfunction that contributes to the underlying pathogenesis of SPG7-HSP.

Early-onset ALS with long-term survival associated with spastin gene mutation.

The authors report a 73-year-old patient with a natural history of early-onset ALS for 49 years presenting with limb and bulbar amyotrophy and a pyramidal syndrome. Analysis of the locus SPG4 identified a heterozygous duplication mutation (c.304_309dupGCCTCG) within exon 1 of the spastin gene. We propose that sequence alterations of spastin may comprise a genetic risk factor in a greater spectrum of motor neuron disorders including clinical variants of ALS.

A study of beta-casein tertiary structure by intramolecular crosslinking and mass spectrometry.

The objective of this study was to obtain experimental evidence to extend the discussion on the 3-D structure of beta-casein (beta-CN). The approach involved the preparation of homobifunctional crosslinkers, bis(sulfosuccinimidyl) derivatives of dicarboxylic acids of several lengths, which specifically react with primary amines of lysinyl residues or the N-terminal in the protein. The intramolecular crosslinks formed were determined by enzymatic digestion and by matrix-assisted laser desorption and ionization time-of-flight mass spectrometry combined with comparison against the theoretical digestion patterns. This procedure allowed the measurement of distances between the crosslinked residues. Ten different masses arising from 8 different specific intramolecular crosslinks were identified. Of these, 5 crosslinks were in good agreement with a published model (Kumosinski et al., 1993). Two other crosslinks each connected 2 residues that are much closer together, according to the model, than the maximum length of the crosslink. However, one of the crosslinks apparently connected 2 residues that are predicted by the model to be 16.7 A farther apart than the crosslink's stretched length. This disparity might be explained by structural flexibility. The structure expressed by the model is probably one of several energetically favorable conformations of the beta-CN molecule, whose structure is best described as rheomorphic rather than either a fixed structure or a random coil.

Surface activity of a synthetic lung surfactant containing a phospholipase-resistant phosphonolipid analog of dipalmitoyl phosphatidylcholine.

Surface activity and sensitivity to inhibition from phospholipase A2 (PLA2), lysophosphatidylcholine (LPC), and serum albumin were studied for a synthetic C16:0 diether phosphonolipid (DEPN-8) combined with 1.5% by weight of mixed hydrophobic surfactant proteins (SP)-B/C purified from calf lung surfactant extract (CLSE). Pure DEPN-8 had better adsorption and film respreading than the major lung surfactant phospholipid dipalmitoyl phosphatidylcholine and reached minimum surface tensions <1 mN/m under dynamic compression on the Wilhelmy balance and on a pulsating bubble surfactometer (37 degrees C, 20 cycles/min, 50% area compression). DEPN-8 + 1.5% SP-B/C exhibited even greater adsorption and had overall dynamic surface tension lowering equal to CLSE on the bubble. In addition, films of DEPN-8 + 1.5% SP-B/C on the Wilhelmy balance had better respreading than CLSE after seven (but not two) cycles of compression-expansion at 23 degrees C. DEPN-8 is structurally resistant to degradation by PLA2, and DEPN-8 + 1.5% SP-B/C maintained high adsorption and dynamic surface activity in the presence of this enzyme. Incubation of CLSE with PLA2 led to chemical degradation, generation of LPC, and reduced surface activity. DEPN-8 + 1.5% SP-B/C was also more resistant than CLSE to direct biophysical inhibition by LPC, and the two were similar in their sensitivity to biophysical inhibition by serum albumin. These findings indicate that synthetic surfactants containing DEPN-8 combined with surfactant proteins or related synthetic peptides have potential utility for treating surfactant dysfunction in inflammatory lung injury.

Less difference between office and ambulatory blood pressure in women than in men both before and during antihypertensive treatment.

In 199 subjects (56% women) with a diastolic blood pressure (BP) of 95-115 mmHg, 5 mg of either amlodipine or felodipine extended release (ER) was given for 4 weeks following 4 weeks of placebo-treatment. BP was measured by conventional clinic BP technique and by 24-h ambulatory BP monitoring (Spacelab 90202/90207). Men and women had identical clinic BP at baseline and it was lowered equally much by 4 weeks of treatment (men: 158/101 and 147/93, women: 159/102 and 149/93 mmHg, respectively). However, ambulatory BP was higher in women than in men both before and after treatment (men: 145/91 and 134/85, women: 149/95 and 140/89 mmHg, respectively, p < 0.05 for both comparisons). The difference between clinic BP and daytime ambulatory BP was higher in men than in women (systolic men: 8.1 +/- 14, women: 3.7 +/- 15 mmHg, respectively, p = 0.04; diastolic men: 5.5 +/- 8.0, women: 2.1 +/- 8.3 mmHg, p = 0.004). The correlation between the treatment effect measured by ambulatory and clinic BP was poor (systolic r = 0.26, p < 0.0001; diastolic r = 0.17, p = 0.03) and was unaffected by exclusion of subjects with normal ambulatory BP. The poor correlation between treatment effects measured as clinic and ambulatory BP is intriguing, and suggests that using ambulatory BP instead of clinic BP for monitoring the treatment of hypertension could affect the clinical outcome.

The reaction of thiolates with 2,3-dibromo-1-propanol revisited: application to the synthesis of bis(fattyalkylthio)propanols.

This work compares two reaction schemes for preparing 2,3-bis(fattyalkylthio)-1-propanols for further synthetic adaptation as hydrophobic analogs of lung surfactant phosphatidylcholines. An attempt to prepare 2,3-bis(fattyalkylthio)-1-propanols based on the previously published methods of Bell and co-workers (B.R. Ganong, C.R. Loomis, Y.A. Hannun, R.M. Bell, 1986. Proc. Natl. Acad. Sci. USA 83, 1184-1188; B.R. Ganong, R.M. Bell, 1987. Methods Enzymol. 141, 313-320; J.P. Walsh, L. Fahrner, R.M. Bell, 1990. J. Biol. Chem. 265, 4374-4381) was found to give the rearranged 1,3-bis(fattyalkylthio)-2-propanols as major products. As a reliable alternative, the reaction of ethyl 2,3-dibromopropionate with 2 equivalents of long chain sodium n-alkanethioates gave the corresponding ethyl 2,3-bis(n-alkylthio)propionates, which were then reduced with LiAlH4 to yield the desired 2,3-bis(fattyalkylthio)-1-propanols. Both 13C and 1H NMR spectroscopy were used to differentiate the two possible 1,3- and 2,3-dithio substituted alcohol products and to rigorously assign their structures.

Effect of amlodipine versus felodipine extended release on 24-hour ambulatory blood pressure in hypertension.

Amlodipine and felodipine are calcium antagonists of the dihydropyridine type. The elimination half-life of amlodipine is longer than that of felodipine. To study whether the different elimination rates of the drugs were reflected in different duration of blood pressure (BP) control, we compared amlodipine and felodipine extended release (ER) by both conventional clinic BP 24 h after drug intake and 24 h ambulatory BP monitoring (ABPM), with special reference to nighttime and morning blood pressure. Two hundred and sixteen patients with primary hypertension (supine diastolic BP, 95 to 115 mm Hg) were randomized to receive amlodipine or felodipine ER in a multicenter study. The starting dose of both drugs was 5 mg. If the target clinic diastolic BP (90 mm Hg) had not been achieved after 4 weeks the dose was increased to 10 mg. Twenty-four-hour ABPM was performed with the subjects taking placebo medication before randomization and after 4 and 8 weeks undergoing active treatment. Significantly more patients responded after 4 weeks of treatment with amlodipine (50%) as compared with felodipine (33%) (P = .013). ABPM during daytime (07:00 to 23:00) was similar during both treatments, but nighttime systolic (P = .026) and diastolic (P = .019) BP was more effectively reduced by amlodipine than by felodipine. After 8 weeks 82% achieved the target pressure with amlodipine and 69% with felodipine (P = .036 for the difference). Amlodipine seems to be more effective than felodipine when the drugs are compared in the same dose, with regard to the effect on clinic BP 24 h after dosing and to ambulatory BP during the night. The longer elimination half-life of amlodipine as compared to felodipine is the probable reason for this finding.

Recurrence rate of streptococcal pharyngitis related to hygienic measures.

OBJECTIVE: To test the hypothesis that treatment failures of streptococcal pharyngotonsillitis may be caused by reinfection by the patients' own streptococci remaining on a toothbrush or in the bedclothes. DESIGN: To elucidate the role of streptococcal contamination of the environment, hygienic measures regarding change of toothbrush and bed linen and washing of toys were given to half of the patients/families. Throat specimens were taken from all the patients before treatment with phenoxymethylpenicillin for 5 days, and the patients were followed-up for 1 month. At a home visit after 6-10 days, throat specimens were taken from the patients and all permanent residents of the home. Environmental samples were taken from pillowcases, floors, toothbrushes, dummies, and toys. SETTING: Six health care centres. SUBJECTS: 114 patients of all ages suffering from group A streptococcal pharyngotonsillitis, and 289 family members. MEASUREMENTS AND MAIN RESULTS: 54 patients/families received hygiene instructions. The total number of recurrences was 40 (35%). There was no difference in treatment failure rate between patients/families that had taken or not taken hygienic measures. CONCLUSIONS: Hygienic measures have no decisive influence on the risk of recurrence of streptococcal pharyngotonsillitis.

Acid-catalyzed plasmenylcholine hydrolysis and its effect on bilayer permeability: a quantitative study.

This laboratory has previously shown (Anderson, V.C. and Thompson, D.H. (1992) Biochim. Biophys. Acta 1109, 33-42; Thompson, D.H., Gerasimov, O.V., Wheeler, J.J., Rui, Y. and Anderson, V.C. (1996) Biochim. Biophys. Acta 1279, 25-34), that plasmenylcholine (1-alk-1'-enyl-2-palmitoyl-sn-glycero-3-phosphocholine; PlsPamCho) liposomes release hydrophilic contents upon photooxidation or acid-catalyzed hydrolysis. We now report the kinetics and chemical mechanism of the acid-catalyzed reaction and its effect on calcein leakage rates. Hydrolysis of the plasmenylcholine vinyl ether linkage generates fatty aldehydes and 1-hydroxy-2-palmitoyl-sn-glycero-3-phosphocholine (lysolipid); HPLC and 1H-NMR experiments establish that the former is readily air-oxidized to fatty acids, while the latter undergoes rapid acid-catalyzed rearrangement to 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine. Lysolipid formation obeys first order kinetics, yielding observed pseudo-first order rate constants that are pH-dependent. Bimolecular hydrolysis rate constants, k(bi), have also been determined. Calcein release rates from plasmenylcholine liposomes are strongly dependent on both the dihydrocholesterol (DHC) content and the extent of PlsPamCho hydrolysis within the bilayer. DHC-free plasmenylcholine liposomes (38 degrees C, pH 2.5) require < 5% PlsPamCho hydrolysis to effect > 50% calcein release within 10 min. The presence of > or = 25 mol% DHC, however, greatly reduces the observed calcein release rate; nearly 30% PlsPamCho hydrolysis is required to effect 50% calcein release over a 70-min period in 6:4 PlsPamCho/DHC liposomes. Bacteriochlorophyll a-sensitized photooxidation of plasmenylcholine liposomes also produces fatty aldehyde and another intermediate, tentatively described as 1-formyl-2-palmitoyl-sn-glycero-3-phosphocholine, that hydrolyzes to form the 1-hydroxy lysolipid. These results have important implications for the quantitative description of lysolipid effects on membrane permeability and on the design of triggerable liposomes for drug delivery.

The role of household contacts in the transmission of group A streptococci.

The intrafamilial spread and recurrence of group A beta-haemolytic streptococci (GAS) infections was investigated. The evaluation was based on 114 patients and their families treated with penicillin for 5 days and followed for 1 month. GAS of the same T-type as that of the isolate from the index case were found in other family members in 33% of the families. Genetic finger-printing using RFLP was performed on 33 of the isolates. The mothers dominated among the index cases, 40 patients experienced recurrences, 27 of them were clinical 28 recurrences occurred within 10 days after the end of treatment. Of 20 T-typed patients with early clinical treatment failures, infected family members were detected in 16 families (p < 0.001). In 19% of the patients GAS could be isolated from the nose. These patients had more ill family members than did other patients. An extensive intrafamilial streptococcal spread was found. Most recurrences of GAS pharyngotonsillitis after penicillin treatment are probably due to "ping pong" infection from family members.

Independent association between fasting plasma insulin and ambulatory blood pressure in 50-year-old women.

The aim of the present study was to investigate correlations between fasting insulin and ambulatory blood pressure in healthy 50-year-old women. Sixty-five women without anti-hypertensive medication were investigated at a Primary Health Care Centre in Enköping, Sweden. Fasting plasma insulin, office blood pressure and heart rate were measured as well as ambulatory blood pressure and heart rate (Spacelab 90202). Log-transformed insulin correlated with all blood pressure recordings (r = 0.3-0.5; p < 0.05) but only with night-time heart rate (r = 0.3; p < 0.05). In multiple regression analyses log-insulin still correlated with night-time systolic blood pressure and heart rate, but not with the other blood pressure variables, after elimination of the influence of body mass index. We conclude that fasting plasma insulin shows an obesity-independent correlation with night-time systolic blood pressure and heart rate in healthy women, possible indicators of a "basic" sympathetic nervous outflow in muscle tissue during sleep.

Three families of thiol peptides are induced by cadmium in maize.

Phytochelatins ((gamma GluCys)nGly) are synthesized from glutathione by plants exposed to metals like Cd2+, Cu2+ and Zn2+. An intracellular complex formed by phytochelatins with Cd2+ and sulfide is thought to detoxify the metal possibly by sequestration in the vacuole. It was found that maize seedlings exposed to Cd2+ produced phytochelatins and two additional families of cysteine-containing peptides, (gamma GluCys)n and (gamma GluCys)nGlu. All thiol peptides with n = 2 and 3 were purified and their structure characterized by tandem mass spectrometry. For maize plants exposed to Cd2+ for 7 days, phytochelatins were synthesized preferentially in the first 24 h whereas the amounts of (gamma GluCys)n and (gamma GluCys)nGlu were the highest thereafter. This was probably due to an initial large pool of glutathione available in control plants compared with a dearth of gamma GluCys and no detectable gamma GluCysGlu. The (gamma GluCys)nGlu peptides were induced exclusively by Cd2+ as they were below the detection limit in control seedlings that contained low amounts of phytochelatins and (gamma GluCys)n. Since the Cys moiety of the peptides is essential for binding Cd2+, a role for accumulated (gamma GluCys)n and (gamma GluCys)nGlu in detoxifying Cd2+ in plants must be considered.

Local and systemic immune response in Helicobacter pylori-associated chronic gastritis before and after treatment.

Ten patients with Helicobacter pylori-associated chronic gastritis were given combination therapy for 6 weeks with a bismuth subnitrate-containing compound and bacampicillin. The eradication rate was 40% 6 weeks after the end of treatment. Two patients remained H. pylori-negative at long-term follow-up after 6 and 17 months; that is, H. pylori was only eradicated in 20% of the patients after long-term observation. By dot blot and immunoblotting both urease and an urease-associated heat shock protein (HSP62) were found to be specific and constant immunodominant H. pylori antigens. The immunohistologic pattern showed induced expression of HLA-DR and HSP62, but not of ICAM-1, in all but two biopsy specimens of gastric epithelial cells. This study suggests i) that long-term observation is important when evaluating the efficacy of anti-H. pylori therapy; ii) that the immune defense mechanisms in the gastric mucosa differ from those in inflammatory conditions affecting other organs, where ICAM-1 and HLA-DR seem to be governed by a common regulator; and iii) that the immunopathologic effects of H. pylori may be caused by autologous and/or bacterial HSPs, which act as triggering factors in the development and persistence of the chronic inflammation in the gastric mucosa.