Treatment of 95 post-Covid patients with SSRIs.

After Covid-19 infection, 12.5% develops post-Covid-syndrome (PCS). Symptoms indicate numerous affected organ systems. After a year, chronic fatigue, dysautonomia and neurological and neuropsychiatric complaints predominate. In this study, 95 PCS patients were treated with selective serotonin reuptake inhibitors (SSRIs). This study used an exploratory questionnaire and found that two-thirds of patients had a reasonably good to strong response on SSRIs, over a quarter of patients had moderate response, while 10% reported no response. Overall, patients experienced substantial improved well-being. Brainfog and sensory overload decreased most, followed by chronic fatigue and dysautonomia. Outcomes were measured with three different measures that correlated strongly with each other. The response to SSRIs in PCS conditions was explained by seven possible neurobiological mechanisms based on recent literature on PCS integrated with already existing knowledge. Important for understanding these mechanisms is the underlying biochemical interaction between various neurotransmitter systems and parts of the immune system, and their dysregulation in PCS. The main link appears to be with the metabolic kynurenine pathway (KP) which interacts extensively with the immune system. The KP uses the same precursor as serotonin: tryptophan. The KP is overactive in PCS which maintains inflammation and which causes a lack of tryptophan. Finally, potential avenues for future research to advance this line of clinical research are discussed.

The Benefits and Harms of Pharmacological Treatment for Postradiation Pelvic Pain: A Systematic Review by the European Association of Urology Chronic Pelvic Pain Panel with Recommendations for Clinical Practice.

Context: Radiotherapy of the pelvis is a widely used method for the treatment of malignancies, and local complications including pain following pelvic radiation therapy are acknowledged complications. Objective: The primary objective is to assess the clinical effectiveness and safety of pharmacological therapies on postradiation pelvic pain. Evidence acquisition: A systematic review of the use of different pharmacological treatments in the management of post-radiation pelvic pain was conducted (PROSPERO-ID: CRD42021249026). Comprehensive searches of EMBASE, Medline, and Cochrane library were performed for publications between January 1980 and April 2021. The primary outcomes were improvement in pain and adverse events following treatment. The secondary outcomes included quality of life, bowel function, and urinary function. Evidence synthesis: After screening 1514 abstracts, four randomised controlled trials were identified, enrolling 355 patients with bladder and anorectal subtypes of postradiotherapy chronic pelvic pain (CPP). A narrative synthesis was performed as heterogeneity of included studies precluded a meta-analysis. A single study reported a significant reduction in pain after 6 mo in patients with bladder pain syndrome treated with hyaluronic acid or hyperbaric oxygen. Anorectal pain was reported to be reduced by the application of 4% formalin, but the use of hyperbaric oxygen in postradiotherapy anorectal pain remains controversial. Adverse event reporting was generally poor. Studies looking at medications used routinely in guidelines for neuropathic pain, such as gabapentin, pregabalin, amitriptyline, and duloxetine, were absent or of poor quality when it came to postradiation pelvic pain. Conclusions: Beneficial effects of hyperbaric oxygen or formalin on pain, quality of life, and functional symptoms were seen in patients with certain CPP subtypes, but the current evidence level is too weak to allow recommendations about the use of any pharmacological treatment for postradiation pelvic pain. Patient summary: Different pharmacological treatments are used to treat pain after radiotherapy, but current studies are of insufficient quality to determine whether these should be recommended and many chronic pelvic pain subtypes are not covered. Further research is needed.

Myofascial Pelvic Pain: Best Orientation and Clinical Practice. Position of the European Association of Urology Guidelines Panel on Chronic Pelvic Pain.

CONTEXT: Despite the high prevalence of a myofascial pain component in chronic pelvic pain (CPP) syndromes, awareness and management of this component are lacking among health care providers. OBJECTIVE: To summarize the current state of the art for the management of myofascial pain in chronic primary pelvic pain syndromes (CPPPS) according to scientific research and input from experts from the European Association of Urology (EAU) guidelines panel on CPP. EVIDENCE ACQUISITION: A narrative review was undertaken using three sources: (1) information in the EAU guidelines on CPP; (2) information retrieved from the literature on research published in the past 3 yr on myofascial pelvic pain; and (3) expert opinion from panel members. EVIDENCE SYNTHESIS: Studies confirm a high prevalence of a myofascial pain component in CPPPS. Examination of the pelvic floor muscles should follow published recommendations to standardize findings and disseminate the procedure. Treatment of pelvic floor muscle dysfunction and pain in the context of CPP was found to contribute to CPP control and is feasible via different physiotherapy techniques. A multidisciplinary approach is the most effective. CONCLUSIONS: Despite its high prevalence, the myofascial component of CPP has been underevaluated and undertreated to date. Myofascial pain must be assessed in all patients with CPPPS. Treatment of the myofascial pain component is relevant for global treatment success. Further studies are imperative to reinforce and better define the role of each physiotherapy technique in CPPPS. PATIENT SUMMARY: Pain and inflammation of the body's muscle and soft tissues (myofascial pain) frequently occurs in pelvic pain syndromes. Its presence must be evaluated to optimize management for each patient. If diagnosed, myofascial pain should be treated.

Quality Evolution and Aroma Profile of Pointed Cabbage in Different Storage Regimes.

With its increasing popularity, the need for optimal storage conditions of pointed cabbages becomes more important to meet the year-round demand. Storage of the pointed varieties, however, is more difficult compared to the traditional, round varieties and is limited to a few weeks in normal air. Pointed cabbages are more susceptible to quality loss (shriveling, yellowing of leaves, weight loss, fungal, and bacterial infections) and tend to spoil much faster. In order to provide a year-round availability of the fresh product, storage under controlled atmosphere (CA) could offer a solution. In this study, pointed, white cabbage heads (Brassica oleracea var. capitata for. alba L. subv. Conica cv. 'Caraflex') were stored at 1°C from November 2018 to May 2019 under four different CA conditions (1 kPa O2 + 1.5 kPa CO2, 1 kPa O2 + 5 kPa CO2, 3 kPa O2 + 1.5 kPa CO2, and 3 kPa O2 + 5 kPa CO2), and compared to storage under normal air. Results showed that CA storage resulted in a prolonged storage life with a good quality retention for both texture and aroma. CA-stored cabbages showed less weight loss, shriveling, and yellowing. Internal quality parameters [color, soluble solids content (SSC)] were stable over the whole storage period for all objects. The aroma profiles of both the storage atmosphere and cabbage samples were impacted by storage duration. The aroma of cabbage juice was also affected by the storage regime. A clear separation was found for cabbage stored under CA compared to the reference group. From the CA-treatments studied, a combination of low oxygen (1 kPa O2) and elevated carbon dioxide levels (5 kPa CO2) showed the best results maintaining quality. Storage under CA resulted in a better resemblance to the aroma of freshly, harvested produce compared to cabbages stored in normal air.

The Benefits and Harms of Botulinum Toxin-A in the Treatment of Chronic Pelvic Pain Syndromes: A Systematic Review by the European Association of Urology Chronic Pelvic Pain Panel.

CONTEXT: Patients with chronic pelvic pain syndrome (CPPS) may have pain refractory to conventional management strategies. Botulinum toxin A (BTX-A) is a potential therapeutic option. OBJECTIVE: To evaluate the benefits and harms of BTX-A injections in the treatment of CPPS. EVIDENCE ACQUISITION: A systematic review of the use of BTX-A in the treatment of CPPS was conducted (PROSPERO-ID: 162416). Comprehensive searches of EMBASE, PUBMED, Medline, and SCOPUS were performed for publications between January 1996 and May 2020. Identified studies were screened and selected studies assessed for quality prior to data extraction. The primary outcomes were improvement in pain and adverse events following treatment. Secondary outcomes included quality of life, global response assessment, sexual function, bowel function, and bladder function. EVIDENCE SYNTHESIS: After screening 1001 abstracts, 16 studies including 11 randomised controlled trials were identified, enrolling 858 patients and covering a range of CPPS subtypes. Most studies showed high risks of bias and confounding across all domains. A narrative synthesis was performed as heterogeneity of included studies precluded a meta-analysis and calculation of pooled effect estimates of measured outcomes. BTX-A reduced pain significantly in patients with bladder pain syndrome in two studies and in patients with prostate pain syndrome in one study, but no included studies showed benefit for patients with gynaecological pelvic pain. Adverse event reporting was variable and generally poor, but no serious adverse events were described. CONCLUSIONS: Beneficial effects of BTX-A on pain, quality of life, and functional symptoms were seen in patients with certain CPPS subtypes, but the current evidence level is too weak to allow recommendations about BTX-A use for treating CPPS. PATIENT SUMMARY: Botulinum toxin A is used to treat different pain disorders, but current studies are of insufficient quality to determine whether it reduces pain and improves quality of life in patients with chronic pelvic pain. Further research is needed.

Management of chronic primary pelvic pain syndromes.

Management of chronic pelvic pain (CPP) remains a huge challenge for care providers and a major burden for healthcare systems. Treating chronic pain that has no obvious cause warrants an understanding of the difficulties in managing these conditions. Chronic pain has recently been accepted as a disease in its own right by the World Health Organization, with chronic pain without obvious cause being classified as chronic primary pain. Despite innumerable treatments that have been proposed and tried to date for CPP, unimodal therapeutic options are mostly unsuccessful, especially in unselected individuals. In contrast, individualised multimodal management of CPP seems the most promising approach and may lead to an acceptable situation for a large proportion of patients. In the present review, the interdisciplinary and interprofessional European Association of Urology Chronic Pelvic Pain Guideline Group gives a contemporary overview of the most important concepts to successfully diagnose and treat this challenging disease.

Cómo fusionar las unidades de ortogeriatría con las unidades de coordinación de fracturas (FLS). Experiencia en el Complejo Sanitario Joan XXIII de Tarragona / How to merge Orthogeriatrics Units with Fracture Coordination Units (FCU). Experience in the Joan XXIII Health Complex of Tarragona

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Unimolecular HBr and HF Elimination Reactions of Vibrationally Excited C2H5CH2Br and C2D5CHFBr: Identification of the 1,1-HBr Elimination Reaction from C2D5CHFBr and Search for the C2D5(F)C:HBr Adduct.

Chemical activation experiments and computational methods have been used to study the unimolecular reactions of C2H5CH2Br and C2D5CHFBr with 90 and 93 kcal mol-1 of vibrational energy, respectively. The four-centered elimination reactions of HBr and DBr are the dominant reactions; however, 2,1-DF, 1,1-HBr, and 1,1-HF reactions are also observed from C2D5CHFBr. The main focus was to search for the role of the C2D5(F)C:HBr adduct in the 1,1-HBr elimination for comparison with carbene adducts in 1,1-HX(Y) elimination from RCHXY (X,Y = Cl and F) molecules. Models of transition states and molecules from electronic structure calculations were used in statistical calculations of the rate constants to assign threshold energies for each reaction based on the experimental rate constants. The threshold energy for 2,1-HBr elimination from 1-bromopropane is 50 kcal mol-1, which is in basic agreement with thermal activation experiments. Comparison of the 2,1-DBr and 2,1-HBr rate constants permits discussion of the kinetic isotope effects and the effect of F atom substitution on the threshold energy for 2,1-HBr elimination. Although CD3CD═CDF from 1,1-HBr elimination of C2D5CHFBr followed by D atom migration is an experimentally observed product, dissociation of the C2D5(F)C:HBr adduct may be the rate-limiting step rather than crossing the barrier associated with the transition state for 1,1-HBr elimination. The calculated dissociation energies of C2H5(X)C:HF adducts are 9.9, 9.3, and 9.0 kcal mol-1 for X = F, Cl, and Br, and the values for C2H5(F)C:HX are 9.9, 6.4, and ∼4.9 kcal mol-1.

A Broadband Mid-Infrared Trace Gas Sensor Using Supercontinuum Light Source: Applications for Real-Time Quality Control for Fruit Storage.

We present a fully integrated and transportable multi-species trace gas sensor based on a mid-infrared (MIR) supercontinuum light source. The high brightness (surpassing synchrotron) and ultra-broad spectral bandwidth (2-4 µm) of this light source allows simultaneous detection of multiple broadband absorbing gas species. High sensitivity in the sub-ppmv level has been achieved by utilizing an astigmatic multipass cell. A grating-based spectrometer at a scanning rate of 20 Hz is developed employing a balanced detection scheme. A multi-component global fitting algorithm is implemented into a central LabVIEW program to perform real-time data analysis. The obtained concentration values are validated by the standard gas chromatography mass spectrometry (GC-MS) method. Field application of the sensor for quality control of stored fruits at a small scale is demonstrated, involving the detection of ethylene, ethanol, ethyl acetate, acetaldehyde, methanol, acetone, and water simultaneously. The sensor also shows promising potentials for other applications, such as environmental monitoring and biomedical research.

A Global Phase I Clinical Study Comparing the Safety and Pharmacokinetics of Proposed Biosimilar BAT1706 and Bevacizumab (Avastin®) in Healthy Male Subjects.

OBJECTIVE: BAT1706 is a proposed biosimilar of bevacizumab (BEV). The objective of this phase I clinical trial was to establish pairwise similarity between BAT1706, US-sourced BEV (US-BEV), and EU-sourced BEV (EU-BEV) after a single intravenous (IV) infusion in healthy male subjects. METHODS: This phase I clinical trial was a randomized, double-blinded, three-arm study in 128 healthy adult male subjects. Every subject received a single IV infusion of 1 mg/kg of study drug and was subsequently monitored for 14 weeks. Pharmacokinetic, safety, and immunogenicity data were collected from each patient. The primary pharmacokinetic endpoint of this clinical study was area under the concentration curve from time zero to infinity (AUC0-inf). Biosimilarity of the study drugs was confirmed if the two-sided 90% confidence interval (CI) ratios of the geometric means for the three pairwise comparisons were contained within the range 80-125%. Other pharmacokinetic parameters including area under the concentration curve to time t (AUC0-t), maximum concentration of drug in plasma (Cmax), half-life (t½), and time to Cmax (tmax) were also measured. RESULTS: The pharmacokinetic parameters were comparable for the three drug products evaluated. The 90% CI for the AUC0-inf was 99-112% for BAT1706 versus EU-BEV, 97-110% for BAT1706 vs US-BEV and 92-104% for EU-BEV versus US-BEV comparisons, respectively, demonstrating biosimilarity. There were no significant adverse events attributable to BAT1706, as compared to EU-BEV and US-BEV. BAT1706 demonstrated a similar safety profile to EU-BEV and US-BEV. In addition, no anti-drug antibody positive result was reported for any subject included in the study. CONCLUSION: In this study, BAT1706, a proposed biosimilar of BEV, was shown to be highly similar to EU-BEV and US-BEV in terms of pharmacokinetic equivalence, safety, and immunogenicity in healthy subjects after a single IV infusion. TRIAL REGISTRATION: NCT03030430.

Experimental and Computational Studies of Unimolecular 1,1-HX (X = F, Cl) Elimination Reactions of C2D5CHFCl: Role of Carbene:HF and HCl Adducts in the Exit Channel of RCHFCl and RCHCl2 Reactions.

The gas-phase unimolecular reactions of C2D5CHFCl molecules with 94 kcal mol-1 of vibrational energy have been studied by the chemical-activation experimental technique and by electronic-structure computations. Products from the reaction of C2D5CHFCl molecules, formed by the recombination of C2D5 and CHFCl radicals in a room temperature bath gas, were measured by gas chromatography-mass spectrometry. The 2,1-DCl (81%) and 1,1-HCl (17%) elimination reactions are the principal processes, but 2,1-DF and 1,1-HF elimination reactions also are observed. Comparison of experimental rate constants to calculated statistical rate constants provides threshold energies. The potential surfaces associated with C2D5(F)C: + HCl and C2D5(Cl)C: + HF reactions are of special interest because hydrogen-bonded adducts with HCl and HF with dissociation energies of 6.4 and 9.3 kcal mol-1, respectively, are predicted by calculations. The relationship between the geometries and threshold energies of transition states for 1,1-HCl elimination and carbene:HCl adducts is complex, and previous studies of related molecules, such as CD3CHFCl, CD2ClCHFCl, C2D5CHCl2, and halogenated methanes are included in the computational analysis. Extensive calculations for CH3CHFCl as a model for 1,1-HCl reactions illustrate properties of the exit-channel potential energy surface. Since the 1,1-HCl transition state is submerged relative to dissociation of the adduct, inner and outer transition states should be considered for analysis of rate constants describing 1,1-HCl elimination and addition reactions of carbenes to HCl.

Analysis of the Five Unimolecular Reaction Pathways of CD2ClCHFCl with Emphasis on CD2Cl(F)C: and CD2Cl(Cl)C: Formed by 1,1-HCl and 1,1-HF Elimination.

The five unimolecular HX and DX (X = F, Cl) elimination pathways of CD2ClCHFCl* were examined using a chemical activation technique; the molecules were generated with 92 kcal mol-1 of vibrational energy in a room-temperature bath gas by a combination of CD2Cl and CHFCl radicals. The total unimolecular rate constant was 9.7 × 107 s-1, and branching fractions for each channel were 0.52 (2,1-DCl), 0.29 (1,1-HCl), 0.10 (2,1-DF), 0.07 (1,1-HF), and 0.02 (1,2-HCl). Comparison of the individual experimental rate constants to calculated statistical rate constants gave threshold energies for each process as 63, 72, 66, 73, and 70 kcal mol-1, listed in the same order as the branching fractions. The 1,1-HCl and 1,1-HF reactions gave carbenes, CD2Cl(F)C: and CD2Cl(Cl)C:, respectively, as products, which have hydrogen-bonded complexes with HCl or HF in the exit channel of the potential energy surface. These carbenes have energy in excess of the threshold energy for D atom migration to give CDCl═CDF and CDCl═CDCl, and the subsequent cis-trans isomerization rates of the dihaloethenes can provide information about energy disposal by the 1,1-HX elimination reactions. Electronic structure calculations provide information for transition states of CD2ClCHFCl and hydrogen-bonded complexes of carbenes with HF and HCl. In addition, D atom migration in both free carbenes and in complexes formed by the carbene hydrogen bonding to HCl or HF is explored.

Down-regulation of respiration in pear fruit depends on temperature.

The respiration rate of plant tissues decreases when the amount of available O2 is reduced. There is, however, a debate on whether the respiration rate is controlled either by diffusion limitation of oxygen or through regulatory processes at the level of the transcriptome. We used experimental and modelling approaches to demonstrate that both diffusion limitation and metabolic regulation affect the response of respiration of bulky plant organs such as fruit to reduced O2 levels in the surrounding atmosphere. Diffusion limitation greatly affects fruit respiration at high temperature, but at low temperature respiration is reduced through a regulatory process, presumably a response to a signal generated by a plant oxygen sensor. The response of respiration to O2 is time dependent and is highly sensitive, particularly at low O2 levels in the surrounding atmosphere. Down-regulation of the respiration at low temperatures may save internal O2 and relieve hypoxic conditions in the fruit.

The Unimolecular Reactions of CF3CHF2 Studied by Chemical Activation: Assignment of Rate Constants and Threshold Energies to the 1,2-H Atom Transfer, 1,1-HF and 1,2-HF Elimination Reactions, and the Dependence of Threshold Energies on the Number of F-Atom Substituents in the Fluoroethane Molecules.

The recombination of CF3 and CHF2 radicals in a room-temperature bath gas was used to prepare vibrationally excited CF3CHF2* molecules with 101 kcal mol-1 of vibrational energy. The subsequent 1,2-H atom transfer and 1,1-HF and 1,2-HF elimination reactions were observed as a function of bath gas pressure by following the CHF3, CF3(F)C: and C2F4 product concentrations by gas chromatography using a mass spectrometer as the detector. The singlet CF3(F)C: concentration was measured by trapping the carbene with trans-2-butene. The experimental rate constants are 3.6 × 104, 4.7 × 104, and 1.1 × 104 s-1 for the 1,2-H atom transfer and 1,1-HF and 1,2-HF elimination reactions, respectively. These experimental rate constants were matched to statistical RRKM calculated rate constants to assign threshold energies (E0) of 88 ± 2, 88 ± 2, and 87 ± 2 kcal mol-1 to the three reactions. Pentafluoroethane is the only fluoroethane that has a competitive H atom transfer decomposition reaction, and it is the only example with 1,1-HF elimination being more important than 1,2-HF elimination. The trend of increasing threshold energies for both 1,1-HF and 1,2-HF processes with the number of F atoms in the fluoroethane molecule is summarized and investigated with electronic-structure calculations. Examination of the intrinsic reaction coordinate associated with the 1,1-HF elimination reaction found an adduct between CF3(F)C: and HF in the exit channel with a dissociation energy of ∼5 kcal mol-1. Hydrogen-bonded complexes between HF and the H atom migration transition state of CH3(F)C: and the F atom migration transition state of CF3(F)C: also were found by the calculations. The role that these carbene-HF complexes could play in 1,1-HF elimination reactions is discussed.

Emergency Medical Service Personnel Recognize Pediatric Concussions.

Concussions are a major cause of morbidity in pediatrics. Many concussions occur during activities with emergency medical service (EMS) providers present to determine if a higher level of care is needed. Data are limited on how capable these providers are. We assessed the ability of EMS providers to recognize pediatric concussions. Fifty-six total responses were included, 38 from EMS and 18 from our MD/RN (medical doctor/registered nurse) group. No statistical differences were found between the 2 groups when adjusted for age, gender, number of years in practice, and number of pediatric concussions managed. This first of its kind pilot study was designed to assess EMS personnel's ability to recognize and triage pediatric concussions. Our findings show EMS providers are statistically identical in their ability to recognize and triage concussions to physicians. The performance of our MD participants was lower than expected. Larger studies are needed to further investigate EMS providers' ability to recognize a concussion.

A mechanistic modelling approach to understand 1-MCP inhibition of ethylene action and quality changes during ripening of apples.

BACKGROUND: 1-Methylcyclopropene (1-MCP) inhibits ripening in climacteric fruit by blocking ethylene receptors, preventing ethylene from binding and eliciting its action. The objective of the current study was to use mathematical models to describe 1-MCP inhibition of apple fruit ripening, and to provide a tool for predicting ethylene production, and two important quality indicators of apple fruit, firmness and background colour. RESULTS: A model consisting of coupled differential equations describing 1-MCP inhibition of apple ripening was developed. Data on ethylene production, expression of ethylene receptors, firmness, and background colour during ripening of untreated and 1-MCP treated apples were used to calibrate the model. An overall adjusted R2 of 95% was obtained. The impact of time from harvest to treatment, and harvest maturity on 1-MCP efficacy was modelled. Different hypotheses on the partial response of 'Jonagold' apple to 1-MCP treatment were tested using the model. The model was validated using an independent dataset. CONCLUSIONS: Low 1-MCP blocking efficacy was shown to be the most likely cause of partial response for delayed 1-MCP treatment, and 1-MCP treatment of late-picked apples. Time from harvest to treatment was a more important factor than maturity for 1-MCP efficacy in 'Jonagold' apples. © 2017 Society of Chemical Industry.

Reinvestigation of the Unimolecular Reactions of CHF2CHF2: Identification of the 1,1-HF Elimination Component from Addition of :CFCHF2 to trans-2-Butene.

The recombination of ·CHF2 radicals in a room-temperature bath gas was used to generate CHF2CHF2* (where * indicates vibrational excitation) molecules with 96 kcal mol-1 of vibrational energy. The CHF2CHF2* molecules decompose by four-centered 1,2-HF elimination and by three-centered 1,1-HF elimination reactions to give HF and either CHF═CF2 or :CFCHF2, respectively. The 1,1-HF component was identified by trapping the :CFCHF2 carbene with trans-2-butene that forms 1-fluoro-1-difluoromethyl-2,3-dimethylcyclopropane. The total rate constant for the decomposition of CHF2CHF2* was 6.0 × 105 s-1, and the rate constant for the 1,1-HF pathway forming the carbene, as measured by the 1-fluoro-1-difluoromethyl-2,3-dimethylcyclopropane yield, was 1.4 × 105 s-1. On the basis of matching the experimental rate constants to calculated statistical rate constants, the threshold energies for the four-centered and three-centered reactions are 78 and ≤85 kcal mol-1, respectively.

Chemical Activation Study of the Unimolecular Reactions of CD3CD2CHCl2 and CHCl2CHCl2 with Analysis of the 1,1-HCl Elimination Pathway.

Chemically activated C2D5CHCl2 molecules were generated with 88 kcal mol-1 of vibrational energy by the recombination of C2D5 and CHCl2 radicals in a room temperature bath gas. The competing 2,1-DCl and 1,1-HCl unimolecular reactions were identified by the observation of the CD3CD═CHCl and CD3CD═CDCl products. The initial CD3CD2C-Cl carbene product from 1,1-HCl elimination rearranges to CD3CD═CDCl under the conditions of the experiments. The experimental rate constants were 2.7 × 107 and 0.47 × 107 s-1 for 2,1-DCl and 1,1-HCl elimination reactions, respectively, which corresponds to branching fractions of 0.84 and 0.16. The experimental rate constants were compared to calculated statistical rate constants to assign threshold energies of 54 and ≈66 kcal mol-1 for the 1,2-DCl and 1,1-HCl reactions, respectively. The statistical rate constants were obtained from models developed from electronic-structure calculations for the molecule and its transition states. The rate constant (5.3 × 107 s-1) for the unimolecular decomposition of CHCl2CHCl2 molecules formed with 82 kcal mol-1 of vibrational energy by the recombination of CHCl2 radicals also is reported. On the basis of the magnitude of the calculated rate constant, 1,1-HCl elimination must contribute less than 15% to the reaction; 1,2-HCl elimination is the major reaction and the threshold energy is 59 kcal mol-1. Calculations also were done to analyze previously published rate constants for chemically activated CD2ClCHCl2 molecules with 86 kcal mol-1 of energy to obtain a better overall description of the nature of the 1,1-HCl pathway for 1,1-dichloroalkanes. The interplay of the threshold energies for the 2,1-HCl and 1,1-HCl reactions and the available energy determines the product branching fractions for individual molecules. The unusual nature of the transition state for 1,1-HCl elimination is discussed.

Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome.

Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands. Furthermore, we studied concordance between tumor IHC/MSI (immunohistochemistry/microsatellite instability) profile and mutation carrier state. Overall, we found 52 different pathogenic PMS2 variants explaining 121 Lynch syndrome and nine CMMRD patients. In vitro mismatch repair assays suggested pathogenicity for three missense variants. Ninety-one PMS2 mutation carriers (70%) showed isolated loss of PMS2 in their tumors, for 31 (24%) no or inconclusive IHC was available, and eight carriers (6%) showed discordant IHC (presence of PMS2 or loss of both MLH1 and PMS2). Ten cases with isolated PMS2 loss (10%; 10/97) harbored MLH1 mutations. We confirmed that recently improved mutation analysis provides a high yield of PMS2 mutations in patients with isolated loss of PMS2 expression. Application of universal tumor prescreening methods will however miss some PMS2 germline mutation carriers.

Slow softening of Kanzi apples (Malus×domestica L.) is associated with preservation of pectin integrity in middle lamella.

Kanzi is a recently developed apple cultivar that has an extremely low ethylene production, and maintains its crispiness during ripening. To identify key determinants of the slow softening behaviour of Kanzi apples, a comparative analysis of pectin biochemistry and tissue fracture pattern during different ripening stages of Kanzi apples was performed against Golden Delicious, a rapid softening cultivar. While substantial pectin depolymerisation and solubilisation was observed during softening in Golden Delicious apples, no depolymerisation or increased solubilisation was observed in Kanzi apples. Moreover, tissue failure during ripening was mainly by cell breakage in Kanzi apples and, in contrast, by cell separation in Golden Delicious apples. Kanzi apples had lower activity of beta-galactosidase, with no decline in the extent of branching of the pectin chain. A sudden decrease in firmness observed during senescence in Kanzi apples was not due to middle lamella dissolution, as tissue failure still occurred by cell breakage.