Andrological findings in infertile men with two (biallelic) CFTR mutations: results of a multicentre study in Germany and Austria comprising 71 patients.

STUDY QUESTION: When should cystic fibrosis transmembrane conductance regulator (CFTR) mutation analysis be recommended in infertile men based on andrological findings? SUMMARY ANSWER: CFTR mutation analysis is recommended in all men with unexplained azoospermia in the presence of normal gonadotropin levels. WHAT IS KNOWN ALREADY: While 80-97% of men with congenital bilateral absence of the vas deferens (CBAVD) are thought to carry CFTR mutations, there is uncertainty about the spectrum of clinical and andrological abnormalities in infertile men with bilallelic CFTR mutations. This information is relevant for evidence-based recommendations to couples requesting assisted reproduction. STUDY DESIGN, SIZE, DURATION: We studied the andrological findings of patients with two CFTR mutations who were examined in one of the cooperating fertility centres in Germany and Austria. In the period of January till July 2019, the completed and anonymized data sheets of 78 adult male patients were returned to and analysed by the project leader at the Institute of Human Genetics in Innsbruck, Austria. PARTICIPANTS/MATERIALS, SETTING, METHODS: Minimum study entry criteria were the presence of two (biallelic) CFTR mutations and results of at least one semen analysis. Andrological assessments were undertaken by standardized data sheets and compared with normal reference values. Seventy-one patients were eligible for the study (n = 30, 42% from Germany, n = 26, 37% from Austria, n = 15, 21% other nations). MAIN RESULTS AND THE ROLE OF CHANCE: Gonadotropin levels (FSH, LH) were normal, 22% of patients had reduced testosterone values. Mean right testis volume was 23.38 ml (SD 8.77), mean left testis volume was 22.59 ml (SD 8.68) and thereby statistically increased compared to normal (P < 0.01). although the means remained in the reference range of 12-25 ml. Semen analysis revealed azoospermia in 70 of 71 (99%) patients and severe oligozoospermia <0.1 × 106/ml in one patient. Four semen parameters, i.e. ejaculate volume, pH, α-glucosidase and fructose values, were significantly reduced (P < 0.01). Only 18% of patients had a palpatory and sonographically diagnosed CBAVD, while in 31% the diagnosis of CBAVD was uncertain, in 12% patients, the vas deferens was present but hypoplastic, and in 39% the vas deferens was normally present bilaterally. Seminal vesicles were not detectable in 37% and only unilaterally present in 37% of patients. Apart from total testes volume, clinical findings were similar in patients with two confirmed pathogenic CFTR mutations (Group I) compared with patients who carried one pathogenic mutation and one CFTR variant of unknown significance (Group II). LIMITATIONS, REASONS FOR CAUTION: We could not formally confirm the in trans position of genetic variants in most patients as no family members were available for segregation studies. Nonetheless, considering that most mutations in our study have been previously described without other rare variants in cis, and in view of the compatible andrological phenotype, it is reasonable to assume that the biallelic genotypes are correct. WIDER IMPLICATIONS OF THE FINDINGS: Our study reveals that CFTR mutation analysis has a broader indication than just the absence of the vas deferens. We recommend to completely sequence the CFTR gene if there is a suspicion of obstructive azoospermia, and to extend this analysis to all patients with unexplained azoospermia in the presence of normal gonadotropin levels. STUDY FUNDING/COMPETING INTEREST(S): German Research Foundation Clinical Research Unit 'Male Germ Cells: from Genes to Function' (DFG CRU326, grants to F.T.). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

The incidence of arm, forearm, and hip osteoporotic fractures during early stage of COVID-19 pandemic.

The study analyzes whether the COVID-19 pandemic affects the incidence of arm, forearm, and hip fractures. Additionally, the change in the overall cost of those fractures treatment was estimated. During the COVID-19 pandemic, the incidence of arm, forearm, and hip fractures and the cost of fracture management are decreased. INTRODUCTION: Purposes of the study were to analyze if COVID-19 pandemic influences the incidence of arm, forearm, and hip osteoporotic fractures and to estimate the changes in costs of their management. METHODS: Data on arm, forearm, and hip fracture incidence were collected for inhabitants aged over 50 years in the district of Tarnowskie Góry and the city of Piekary Slaskie, South Poland, in the early stage of COVID-19 pandemic (77 days, from March 16th to May 31st 2020). These results were compared with the number of fractures noted in years 2015-2019 in the same period of the year. The ratio of analyzed fractures per 100,000 inhabitants was calculated. RESULTS: The recorded numbers of fractures of arm, forearm, and hip were 13, 43, and 29, respectively. The respective mean number for fractures reported in corresponding period in 2015-2019 years was 23.6, 52, and 33. The year fracture incidence calculated per 100,000 inhabitants decreased by 45.8%, 18.4%, and 13.4%, respectively. The estimated numbers of avoided fractures extrapolated for the whole country for arm, forearm, and hip were 1722, 1548, and 947, respectively. The total number of avoided fractures was 4217. The expected nationwide cost reduction for the arm, forearm, and hip fracture management was estimated at € 568,260, € 332,820, and € 1,628,840, respectively. The total cost reduction was € 2,529,920 over the period of observation. CONCLUSION: During COVID-19 pandemic, a decrease of arm, forearm, and hip fracture incidence was observed which may result in decrease of total costs for Polish healthcare system.

Electron localization following attosecond molecular photoionization.

For the past several decades, we have been able to directly probe the motion of atoms that is associated with chemical transformations and which occurs on the femtosecond (10(-15)-s) timescale. However, studying the inner workings of atoms and molecules on the electronic timescale has become possible only with the recent development of isolated attosecond (10(-18)-s) laser pulses. Such pulses have been used to investigate atomic photoexcitation and photoionization and electron dynamics in solids, and in molecules could help explore the prompt charge redistribution and localization that accompany photoexcitation processes. In recent work, the dissociative ionization of H(2) and D(2) was monitored on femtosecond timescales and controlled using few-cycle near-infrared laser pulses. Here we report a molecular attosecond pump-probe experiment based on that work: H(2) and D(2) are dissociatively ionized by a sequence comprising an isolated attosecond ultraviolet pulse and an intense few-cycle infrared pulse, and a localization of the electronic charge distribution within the molecule is measured that depends-with attosecond time resolution-on the delay between the pump and probe pulses. The localization occurs by means of two mechanisms, where the infrared laser influences the photoionization or the dissociation of the molecular ion. In the first case, charge localization arises from quantum mechanical interference involving autoionizing states and the laser-altered wavefunction of the departing electron. In the second case, charge localization arises owing to laser-driven population transfer between different electronic states of the molecular ion. These results establish attosecond pump-probe strategies as a powerful tool for investigating the complex molecular dynamics that result from the coupling between electronic and nuclear motions beyond the usual Born-Oppenheimer approximation.

Probing single-photon ionization on the attosecond time scale.

We study photoionization of argon atoms excited by attosecond pulses using an interferometric measurement technique. We measure the difference in time delays between electrons emitted from the 3s(2) and from the 3p(6) shell, at different excitation energies ranging from 32 to 42 eV. The determination of photoemission time delays requires taking into account the measurement process, involving the interaction with a probing infrared field. This contribution can be estimated using a universal formula and is found to account for a substantial fraction of the measured delay.

Phase measurement of resonant two-photon ionization in helium.

We study resonant two-color two-photon ionization of helium via the 1s3p (1)P(1) state. The first color is the 15th harmonic of a tunable Ti:sapphire laser, while the second color is the fundamental laser radiation. Our method uses phase-locked high-order harmonics to determine the phase of the two-photon process by interferometry. The measurement of the two-photon ionization phase variation as a function of detuning from the resonance and intensity of the dressing field allows us to determine the intensity dependence of the transition energy.

Attosecond electron spectroscopy using a novel interferometric pump-probe technique.

We present an interferometric pump-probe technique for the characterization of attosecond electron wave packets (WPs) that uses a free WP as a reference to measure a bound WP. We demonstrate our method by exciting helium atoms using an attosecond pulse (AP) with a bandwidth centered near the ionization threshold, thus creating both a bound and a free WP simultaneously. After a variable delay, the bound WP is ionized by a few-cycle infrared laser precisely synchronized to the original AP. By measuring the delay-dependent photoelectron spectrum we obtain an interferogram that contains both quantum beats as well as multipath interference. Analysis of the interferogram allows us to determine the bound WP components with a spectral resolution much better than the inverse of the AP duration.

Treatment of autochthonous rat colonic adenocarcinomas with a thioether-lysophospholipid derivative in mono- and combination chemotherapy.

In 361 Sprague-Dawley rats autochthonous colorectal carcinomas were induced by intrarectal application of the carcinogen AMMN. Tumor-bearing animals were treated with a synthetic thioether-lysophospholipid (TLP) derivative and in combination chemotherapy with 5-fluorouracil (5-FU) and carmustine (BCNU). There was no difference in the survival time of treated and untreated animals. The median large-bowel tumor weight was significantly lower in the TLP/5-FU and TLP/5-FU/BCNU combination therapy groups than in the control groups. Transient hepatotoxicity was observed in the high-dosage (50 mg/kg body weight twice weekly) TLP group. This study confirmed the relative resistance of AMMN-induced colorectal carcinomas to antineoplastic treatment.

Evaluation of immunogenicity and efficacy of anthrax vaccine adsorbed for postexposure prophylaxis.

Antimicrobials administered postexposure can reduce the incidence or progression of anthrax disease, but they do not protect against the disease resulting from the germination of spores that may remain in the body after cessation of the antimicrobial regimen. Such additional protection may be achieved by postexposure vaccination; however, no anthrax vaccine is licensed for postexposure prophylaxis (PEP). In a rabbit PEP study, animals were subjected to lethal challenge with aerosolized Bacillus anthracis spores and then were treated with levofloxacin with or without concomitant intramuscular (i.m.) vaccination with anthrax vaccine adsorbed (AVA) (BioThrax; Emergent BioDefense Operations Lansing LLC, Lansing, MI), administered twice, 1 week apart. A significant increase in survival rates was observed among vaccinated animals compared to those treated with antibiotic alone. In preexposure prophylaxis studies in rabbits and nonhuman primates (NHPs), animals received two i.m. vaccinations 1 month apart and were challenged with aerosolized anthrax spores at day 70. Prechallenge toxin-neutralizing antibody (TNA) titers correlated with animal survival postchallenge and provided the means for deriving an antibody titer associated with a specific probability of survival in animals. In a clinical immunogenicity study, 82% of the subjects met or exceeded the prechallenge TNA value that was associated with a 70% probability of survival in rabbits and 88% probability of survival in NHPs, which was estimated based on the results of animal preexposure prophylaxis studies. The animal data provide initial information on protective antibody levels for anthrax, as well as support previous findings regarding the ability of AVA to provide added protection to B. anthracis-infected animals compared to antimicrobial treatment alone.

Molecular dissociative ionization and wave-packet dynamics studied using two-color XUV and IR pump-probe spectroscopy.

We present a combined theoretical and experimental study of ultrafast wave-packet dynamics in the dissociative ionization of H_{2} molecules as a result of irradiation with an extreme-ultraviolet (XUV) pulse followed by an infrared (IR) pulse. In experiments where the duration of both the XUV and IR pulses are shorter than the vibrational period of H_{2};{+}, dephasing and rephasing of the vibrational wave packet that is formed in H_{2};{+} upon ionization of the neutral molecule by the XUV pulse is observed. In experiments where the duration of the IR pulse exceeds the vibrational period of H_{2};{+} (15 fs), a pronounced dependence of the H;{+} kinetic energy distribution on XUV-IR delay is observed that can be explained in terms of the adiabatic propagation of the H_{2};{+} wave packet on field-dressed potential energy curves.

Coherent electron scattering captured by an attosecond quantum stroboscope.

We demonstrate a quantum stroboscope based on a sequence of identical attosecond pulses that are used to release electrons into a strong infrared (IR) laser field exactly once per laser cycle. The resulting electron momentum distributions are recorded as a function of time delay between the IR laser and the attosecond pulse train using a velocity map imaging spectrometer. Because our train of attosecond pulses creates a train of identical electron wave packets, a single ionization event can be studied stroboscopically. This technique has enabled us to image the coherent electron scattering that takes place when the IR field is sufficiently strong to reverse the initial direction of the electron motion causing it to rescatter from its parent ion.

Broadband attosecond pulse shaping.

We use semiconductor (Si) and metallic (Al, Zr) transmission filters to shape, in amplitude and phase, high-order harmonics generated from the interaction of an intense titanium sapphire laser field with a pulsed neon gas target. Depending on the properties of the filter, the emitted attosecond pulses can be optimized in bandwidth and/or pulse length. We demonstrate the generation of attosecond pulses centered at energies from 50 to 80 eV, with bandwidths as large as 45 eV and with pulse durations compressed to 130 as.

Modulation of oxidative DNA damage repair by the diet, inflammation and neoplastic transformation.

Oxidative DNA damage and DNA repair may mediate several cellular processes, like replication and transcription, mutagenesis and apoptosis and thus may be important for the organism development as well as its pathogenesis, including cancer. Activity of DNA repair enzymes can depend on many factors, such as gene polymorphism, mRNA and protein level, as well as enzymes activation and inhibition. Modulation of base excision repair pathway eliminating from DNA oxidatively formed lesions may be caused by the diet, inflammation and neoplastic transformation. Reactive oxygen species and some diet components induce transcription of several Base Excision Repair enzymes, e.g. major human AP-endonuclease, (APE1) and 8-oxoG-DNA glycosylase (OGG1). The carcinogenic process in human lung decreases repair activity for 8-oxoGin transcription independent manner, but increases repair activity of epsilon A and epsilon C, as measured in tumors and unchanged lung tissues of lung cancer patients. Thus, modulation of repair enzymes activities may be a cell response on their way to differentiation ot neoplastic transformation.

[The effects of occluding dysfunction on marginal parodontopathies]. / Efectul disfunctiei ocluzale asupra parodontiului marginal.

Occluding dysfunction (occluding dysharmony, occluding trauma) is an important etiologic factor of parodontal disease. It is an integrating element of the destructive process which characterizes the parodontal disease. Occluding dysfunction does not trigger gingivitis, or the development of parodontal pouches, but it does exert an influence on the progress and the importance of parodontal pouches determined by local irritation due to tartar and to bacterial plaques. Occluding dysfunction and the inflammation of parodontal tissues are different processes which occur in the course of the same disease namely of marginal parodonthitis. The inflammation develops in the gums and propagates in the parodontal sustaining tissues. Occluding dysfunction (also known as occluding dysharmony or occluding trauma) occurs in the parodontal sustaining tissues, and both determine tissue destruction. Occluding dysfunction and inflammation become codestructive factors which are interconnected, and are both capable to determine clinical and radiologic changes which are typical for diseased marginal parodontium. Due to the fact that individuals have variable parodontal reactions to local irritation factors, and considering the fact that inflammation and occluding dysfunction occur together but with variable degrees of severity, it is possible that they will not determine in all cases intraosseus pouches with angular lesions, or crater-like lesions. However, when we are confronted with such lesions it is very likely that the combined effects of inflammation and occluding dysfunction are at the origin.

[Absolute bioavailability of a special sustained-release acetylsalicylic acid formulation]. / Absolute Bioverfügbarkeit einer speziellen, retardierten Acetylsalicylsäure-Zubereitung.

Absolute Bioavailability of a Special Acetylsalicylic Acid Sustained Release Formulation. The absolute bioavailability of an acetylsalicylic acid (ASA) sustained release formulation (Contrheuma retard), containing 300 mg ASA as initial dose and 350 mg in a retard formulation, was determined in comparison to a standard ASA solution for intravenous administration in a two-treatment, two-period cross-over trial with 6 healthy male volunteers by comparing the areas under the plasma-fluctuation-time curves of the primary metabolite. In addition, it was examined by comparison of the mean times after administration of both formulations, whether the test formulation meets the requirements of a sustained release formulation. The investigations led to the following results: The absolute bioavailability of the test formulation was 95%. The statistical comparison of the areas under the concentration-time courses allowed no decision (neither for equivalence nor difference). The maximal concentration of SA after intravenous administration of the standard formulation was reached after 0.4 h on an average and amounted to 62 micrograms/ml. After oral administration of the test formulation, a mean concentration maximum of 28 micrograms/ml was calculated, which had been reached after about 2 h. The differences are statistically significant. The mean time for SA was 6 h after the standard formulation, whereas after administration of the test compound, a mean of 11.5 h was calculated. 24 h following administration, the concentration of SA was 1.3 micrograms/ml after intravenous administration of the standard formulation and 5.5 micrograms/ml after administration of the test formulation. These differences, too, are statistically significant. From the comparison of the mean time for SA, a retard factor of 1.9 was calculated.

[Significance of hypertrophy, and of hyperplasia with gingival-periodontal localization]. / Semnificatia hipertrofieie si hiperplaziei cu localizare gingivoparadontala.

The authors have attempted a study of gingival hypertrophy and hyperplasia as a particular manifestation involving the marginal parodontium, manifested clinically as a proliferative process that could be determined by a variety of local or general etiopathogenic factors. An analysis is made of hypertrophic and hyperplastic changes from the histopathologic and the etiologic viewpoints, of the gingivo-parodontal tissues. A review is also presented of several complete classifications. Clinical and histopathologic aspects are further discussed, of the various forms of gingivo-parodontal hyperplasias. Results obtained in the treatment of 160 forms of hyperplasia found in 1500 patients that were investigated are also discussed. The study concludes on the importance of an early diagnosis of various forms of gingivo-parodontal hyperplasias. This is of particular importance for the treatment of those patients where the therapy is directed against the causative agent, but that should also include the application of antiinflammatory therapies.

[Effect of chamomile on wound healing--a clinical double-blind study]. / Wirkung der Kamille in der Wundheilung--eine klinische Doppelblindstudie.

In a double-blind trial, the therapeutic efficacy of chamomile extract was tested on 14 patients. As objective parameters served the epithelial and drying effect on weeping wound area after dermabrasion of tattoos. The period of the healing and drying process was judged by the doctor. The decrease of the weeping wound area as well as the drying tendency was statistically significant.