The changing landscape of SARS-CoV-2: Implications for the maternal-infant dyad.

The COVID-19 pandemic represents the greatest challenge to date faced by the medical community in the 21st century. The rate of rapid dissemination, magnitude of viral contagiousness, person to person transmission at an asymptomatic phase of illness pose a unique and dangerous challenge for all patients, including neonatal and obstetric patients. Although scientific understanding of the pathophysiology of the disease, nature of transmission, and efficacy of mitigation strategies is growing, neither a cure or vaccine have been developed. While COVID-19 is primarily a disease of older patients, infection is now seen across all age demographics with reports of illness in pregnant patients and infants. Altered hormone status and predominance of Th-2 immune helper cells may result in increased predisposition to SARS-CoV-2. Case reports of pregnant patients demonstrate a clinical presentation comparable to non-pregnant adults, but evidence of vertical transmission to the fetus is controversial. Neonatal reports demonstrate an inconsistent and non-specific phenotype, and it is often difficult to separate COVID-19 from the underlying conditions of prematurity or bacterial infection. The development of international registries to enable risk profiling of COVID-19 positive pregnant mothers and/or their offspring may facilitate the development of enhanced mitigation strategies, medical treatments and effective vaccinations.

Amyloid PET imaging in Alzheimer's disease: a comparison of three radiotracers.

PURPOSE: The increasing use of amyloid PET in Alzheimer's disease research and clinical trials has motivated efforts to standardize methodology. We compared retention of the (11)C radiotracer Pittsburgh Compound B (PiB) and that of two (18)F amyloid radiotracers (florbetapir and flutemetamol) using two study populations. We also examined the feasibility of converting between tracer-specific measures, using PiB as the common link between the two (18)F tracers. METHODS: One group of 40 subjects underwent PiB and flutemetamol imaging sessions and a separate group of 32 subjects underwent PiB and florbetapir imaging sessions. We compared cortical and white matter retention for each (18)F tracer relative to that of PiB, as well as retention in several reference regions and image analysis methods. Correlations between tracer pairs were used to convert tracer-specific threshold values for amyloid positivity between tracers. RESULTS: Cortical retention for each pair of tracers was strongly correlated regardless of reference region (PiB-flutemetamol, ρ = 0.84-0.99; PiB-florbetapir, ρ = 0.83-0.97) and analysis method (ρ = 0.90-0.99). Compared to PiB, flutemetamol had higher white matter retention, while florbetapir had lower cortical retention. Two previously established independent thresholds for amyloid positivity were highly consistent when values were converted between tracer pairs. CONCLUSION: Despite differing white and grey matter retention characteristics, cortical retention for each (18)F tracer was highly correlated with that of PiB, enabling conversion of thresholds across tracer measurement scales with a high level of internal consistency. Standardization of analysis methods and measurement scales may facilitate the comparison of amyloid PET data obtained using different tracers.

Coping in Parkinson's disease: an examination of the coping inventory for stressful situations.

BACKGROUND: Parkinson's disease (PD) brings with it a range of stresses and challenges with which a patient must cope. The type of coping strategies employed can impact upon well-being, although findings from coping studies in PD remain inconsistent. The variety of coping scales used without validation in PD has been cited as a possible cause of this inconsistency. The present study sought to examine the validity of the coping inventory for stressful situations (CISS) in a sample of patients with PD. METHODS: Five hundred and twenty-five patients with PD were recruited as part of a longitudinal investigation of mood states in PD. Four hundred and seventy-one participants completed the CISS. Confirmatory factor analysis was used to explore the structural validity of the scale. Internal reliability, test-retest reliability, convergent validity and discriminant validity were assessed using Cronbach's alpha, intraclass correlations and Pearson's correlations. RESULTS: Both three and four factor solutions were examined. The four factor model was found to provide a better fit of the data than the three factor model. The internal reliability, discriminant validity, convergent validity, and test-retest reliability of the CISS scales were shown to be good. Use of emotion-focused coping was associated with greater depression and anxiety whilst, task-oriented coping was associated with better psychological well-being. CONCLUSION: The results provide support for the validity and reliability of the CISS as a measure of coping in patients with PD. Further research into the relationship between coping and well-being is warranted. The identification of helpful and unhelpful coping strategies may guide the development of evidence-based therapies to improve well-being in patients with PD.

Plasma fatty acids of neonates born to mothers with and without gestational diabetes.

Women with gestational diabetes mellitus (GDM) and their neonates have lower levels of arachidonic (AA) and docosahexaenoic (DHA) acids in red cell membranes. It is not clear if this abnormality is restricted to red cells or is a generalised problem. We have investigated plasma fatty acids of neonates (venous cord) of GDM (n=37), and non-diabetic (n=31) women. The GDMs had lower levels of dihomogamma-linolenic (20:3n-6, DHGLA) acid, summation operator n-6 metabolites, DHA and summation operator n-3 metabolites (p<0.05) in choline phosphoglycerides (CPG). They also had lower levels of AA (-4.5%), adrenic acid (22:4n-6, -13%), osbond acid (22:5n-6, -7%) and summation operator n-6 (-2.5%). There was a similar pattern in triglycerides (TG) and cholesterol esters (CE). Mead acid, a marker of generalised shortage of derived and parent essential fatty acids, was higher in CPG and TG of the GDM group by 73% and 76%. The adrenic/osbond acid (22:4n-6/22:5n-6) ratio, a biochemical marker of DHA insufficiency, was reduced in CPG (-4.5%), TG (-63%) and CE (-75%) of the GDM group. These findings, which are consistent with the previous red cell data, suggest that the neuro-visual and vascular development and function of the offspring of GDM women may be adversely affected if the levels of AA and DHA are compromised further by other factors, pre- or post-natally. Studies are required to elucidate the underlying mechanism for the reduction of the two fatty acids and to evaluate the developmental and health implications.

MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo.

The neuropathology of Parkinson's disease is reflected in experimental animals treated with the selective nigrostriatal dopaminergic neurotoxin MPTP. Neurons exposed to MPTP (MPP(+)) express morphological features of apoptosis, although the intracellular pathways that produce this morphology have not been established. The c-Jun NH(2)-terminal kinase (JNK) signaling cascade has been implicated as a mediator of MPTP-induced apoptotic neuronal death based on the ability of CEP-1347/KT-7515, an inhibitor of JNK activation, to attenuate MPTP-induced nigrostriatal dopaminergic degeneration. In these studies, MPTP-mediated activation of the JNK signaling pathway was assessed in the nigrostriatal system of MPTP-treated mice. MPTP elevated levels of phosphorylated JNK and JNK kinase (MKK4; also known as SEK1 or JNKK), by 2.5- and fivefold, respectively. Peak elevations occurred soon after administration of MPTP and coincided with peak CNS levels of MPP(+). Increased MKK4 phosphorylation, but not JNK phosphorylation, was found in the striatum, suggesting that activation of MKK4 occurs in injured dopaminergic terminals. Both JNK and MKK4 phosphorylations were attenuated by pretreatment with l-deprenyl, indicating that these phosphorylation events were mediated by MPP(+). Moreover, CEP-1347/KT-7515 inhibited MPTP-mediated MKK4 and JNK signaling at a dose that attenuates MPTP-induced dopaminergic loss. These data implicate this signaling pathway in MPTP-mediated nigrostriatal dopaminergic death and suggest that it may be activated in the degenerative process in Parkinson's disease.

External exposure to radionuclides accumulated in shoreline sediments with an application to the lower Clinch River.

A simple analytical method was developed to estimate external doses from exposure to contaminated riverine shorelines. The method consists of deriving an adjustment factor that accounts for the geometry of the riverine shoreline; the adjustment factor is applied to the dose-rate coefficients already available for infinite contaminated surfaces. Such a geometry factor circumvents very complex radiation transport calculations which would otherwise be necessary to model exposures to a finite contaminated surface. For instance, for radionuclides emitting gamma rays of energies above 600 keV (e.g., 137Cs), the published dose-rate coefficients must be reduced by 75%, 60%, 50%, and 33% for shoreline widths of 4, 10, 20, and 50 m, respectively. The geometry factor changes only mildly with the energy of the gamma radiation. This property allows for the geometry factor to be used for radionuclides emitting multiple gamma rays of various energies. If a quick analysis is desired, the geometry factors derived for 137Cs can be used for all radionuclides. More refined analysis can be performed by deriving geometry factors for each radionuclide according to its gamma spectrum. Also, the mild variation with energy allows the geometry factors to be applied to the case when radionuclides are accumulated in layers under the soil surface, and not only to the case when radionuclides are deposited onto the soil surface. Empirical relationships between the geometry factor and the dimension of the shoreline were provided so that one can obtain values of the geometry factor for any shoreline width. These relationships can be easily used to account for the uncertainty in the dimension of the shoreline. The method was applied to derive similar adjustment factors for contaminated surfaces of other simple geometries (e.g., circular surfaces). An example of how this method can be applied to its full extent is presented for the case of external exposure to the shores of the lower Clinch River. This river received large amounts of 137Cs, 60Co, 106Ru, 95Zr, 95Nb, 144Ce, and 90Sr released during 1944-1991 from the Oak Ridge Reservation in Oak Ridge, Tennessee.

Isolation of juvenile hormone esterase and its partial cDNA clone from the beetle, Tenebrio molitor.

Juvenile hormone esterase (JHE) plays an essential role in insect development. It is partially responsible for the clearance of juvenile hormone (JH) which regulates various aspects of insect development and reproduction. Because of its role in regulating JH titer, this enzyme has been targeted for development of biologically-based insecticides. JHE was partially purified from the beetle, Tenebrio molitor, using a transition state analog as the affinity ligand. Two forms of JHE were characterized by activity analysis, isoelectric focusing, two-dimensional SDS-PAGE and N-terminal sequence analysis. The esterase is associated with two proteins of sizes 71 and 150 kDa, both of which are active on JH III. A partial cDNA clone for the enzyme was isolated based on the sequence of N-terminal and internal peptides. Its sequence indicates that JHE from T. molitor and Heliothis virescens may have a common origin.

Homology model of juvenile hormone esterase from the crop pest, Heliothis virescens.

Juvenile Hormone Esterase (JHE) plays an essential role in the development of insects since it is partially responsible for clearing juvenile hormone (JH), one of the hormones that is responsible for insect metamorphosis. JHE is a 60 kDa enzyme that selectively hydrolyzes the alpha/beta unsaturated ester of JH. Because of its pivotal role in insect development, we have targeted JHE for use as a biopesticide. In this study, we have constructed a homology-based molecular model of JHE from the agricultural crop pest, Heliothis virescens. JHE is a member of the alpha/beta hydrolase fold family of enzymes and was built according to two structures in the same family: acetylcholinesterase from Torpedo californica and lipase from Geotrichum candidum. Analysis of the active site region reveals extensive conservation between JHE and its templates. A surprise was the presence of a conserved Ser near the catalytic triad. Docking of JH III into the active site has provided insight into protein-substrate interactions that are corroborated by experimental observation. The model is being used as a predictive basis to design biopesticides. In this regard, we have identified a site on the protein surface that is suggestive of a recognition site for the putative JHE receptor.

Rapid purification and molecular modeling of AaIT peptides from venom of Androctonus australis.

As recombinant viruses expressing scorpion toxins are moving closer toward the market, it is important to obtain large amounts of pure toxin for biochemical characterization and the evaluation of biological activity in nontarget organisms. In the past, we purified a large amount of Androctonus australis anti-insect toxin (AaIT) present in the venom of A. australis with an analytical reversed-phase column by repeated runs of crude sample. We now report 20 times improved efficiency and speed of the purification by employing a preparative reversed-phase column. In just two consecutive HPLC steps, almost 1 mg of AaIT was obtained from 70 mg crude venom. Furthermore, additional AaIT was obtained from side fractions in a second HPLC run. Recently discovered insect selective toxin, AaIT5, was isolated simultaneously from the same venom batch. It shows different biological toxicity symptoms than the known excitatory and depressant insect toxins. AaIT5 gave 100% mortality with a dose of less than 1.3 micrograms against fourth-instar tobacco budworms Heliothis virescens 24 h after injection. During the purification process, we implemented mass spectrometry in addition to bioassays to monitor the presence of AaIT and AaIT5 in the HPLC fractions. Mass spectrometric screening can unambiguously follow the purification process and can greatly facilitate and expedite the downstream purification of AaIT and AaIT5 eliminating the number of bioassays required. Further, electrospray ionization was compared with matrix-assisted desorption/ionization and evaluated as a method of choice for mass spectrometric characterization of fractions from the venom purification for it provided higher mass accuracy and relative quantitation capability. Molecular models were built for AaIT5, excitatory toxin AaIT4, and depressant toxin LqhIT2. Three-dimensional structure of AaIT5 was compared with structures of the other two toxins, suggesting that AaIT5 is similar to depressant toxins.

Interval cancers and cancers in non-attenders in the Ostergötland Mammographic Screening Programme. Duration between screening and diagnosis, S-phase fraction and distant recurrence.

The study was based on a population mammographic screening programme for women aged 40-74 years. Metastatic potential was analysed in 843 invasive breast cancers with regard to mode of detection and a number of prognostic factors. There was a higher metastatic capacity in clinically detected cases, but multivariate analyses showed that neither the mode of detection (hazard rate ratio of distant recurrence RR = 1.39, 95% CI 0.78-2.46 interval cancers and RR = 1.6, 95% CI 0.76-3.36 non-attenders) nor the duration between screening and diagnosis for true interval cancers (RR = 0.47, 95% CI 0.16-1.35 in tumours detected later than one year after screening) were independent prognostic factors. A correlation was found between metastatic potential and the SPF (RR = 2.94, 95% CI 1.57-5.50 in tumours with a high SPF), the oestrogen receptor status and the tumour stage. In conclusion, interval cancers intrinsically are not different from other breast cancers with equivalent characteristics; the duration between screening and diagnosis in interval cancers was not clearly correlated to the prognosis, but the S-phase fraction was a powerful predictor of prognosis.

Evaluation of media advocacy efforts within a community trial to reduce alcohol-involved injury. Preliminary newspaper results.

This article examines coverage of alcohol-related topics in local newspapers as applied to a conceptual model of media advocacy being tested in a five-component community trial to reduce alcohol-involved injuries. Based on a literature review of determinants of exposure of newspaper articles, it uses a composite measure that takes into account the likelihood that given articles will be read. This measure is evaluated in terms of the timing of media advocacy training, technical consultation, and resulting media advocacy efforts. Three hypotheses find support. First, postintervention levels of coverage across experimental communities appear generally higher than similar preintervention coverage. Second, although postintervention local and county coverage appears higher across experimental communities, no equivalent effect is present across comparison communities. Third, increases in local and county coverage in experimental communities were not matched by increases in state and national coverage in these communities.

The role of rat serum carboxylesterase in the activation of paclitaxel and camptothecin prodrugs.

Paclitaxel-2-ethylcarbonate (PC) is a prototype for a family of paclitaxel prodrugs that have significant levels of antitumor activities in rodent models for human cancer. In this study, an enzyme responsible for the conversion of PC to paclitaxel was purified from rat serum. N-terminal amino acid sequence analysis indicated that the isolated enzyme was rat serum carboxylesterase. This enzyme was shown to significantly enhance the cytotoxic activities of both PC and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), a water-soluble analogue of camptothecin, on lung carcinoma and melanoma cell lines. Rat serum carboxylesterase may have applications for the site-specific delivery of anticancer drugs to tumor masses.

N5-methylasparagine and energy-transfer efficiency in C-phycocyanin.

A posttranslationally methylated asparagine residue, N5-methylasparagine, is found at the beta-72 site in many phycobiliproteins. Two mutations (Asp and Gln) in the beta-72 position of Agmenellum quadruplicatum C-phycocyanin were investigated to clarify the role of the wild-type N5-methylasparagine near the beta-84 "fluorescing" bilin tetrapyrrole chromophore. Chemical analysis for amide modification revealed that the beta-72Q protein was partially methylated with a stoichiometry of 0.27, suggesting that either the asparagine methyltransferase is nonspecific or a glutamine methyltransferase exists. Urea denaturation studies could detect no difference in protein stability for any of the C-phycocyanin species. Steady-state spectroscopic measurements demonstrate that Asp and Gln substitution for the C-phycocyanin beta-72 NMA affects both the ground to excited state transition and the excited-state characteristics of the beta-84 chromophore, while the rate of radiative energy transfer is unaffected. Energy-transfer efficiency within phycobilisomes (represented by steady-state fluorescence quantum yields) was also negatively impacted by the beta-72 substitutions. Time-resolved fluorescence emission spectroscopic studies with C-phycocyanin reveal three distinguishable fluorescence lifetimes. The longest fluorescence lifetime is diminished 7-10% by the Asp and Gln mutations in comparison to a control sample where beta-72 is NMA. Molecular dynamics calculations implicate a change in the bilin tetrapyrrole chromophore ring geometry as a likely source of the altered photophysics induced by the mutations. We conclude that N5-methylasparagine plays a special role in establishing the environment surrounding the beta-84 chromophore which minimizes the rates of nonradiative energy losses that would otherwise defeat the high quantum yield for energy transfer within the phycobilisomes.

Is psychological wellbeing impaired in long-term survivors of breast cancer?

OBJECTIVE: To measure anxiety and depression in long term survivors of breast cancer. DESIGN: Case-control study. SETTING: Follow up of the trial of early detection of breast cancer in the South West Surrey Health District. SUBJECTS: 331 patients with breast cancer aged 50-78, attending mammographic follow up, who had been invited to screening before diagnosis, and 584 controls who had attended the same clinic but did not have breast cancer. The sample included 290 pairs matched by screening attendance pattern and year of birth. MAIN OUTCOME MEASURE: Anxiety and depression scores on the Hospital Anxiety and Depression Scale. RESULTS: Significantly fewer symptoms of anxiety and depression were reported by patients with cancer than by controls and significantly fewer had high scores suggesting the presence of psychological morbidity meriting treatment. Among the patients with cancer anxiety was more common at the first annual follow up than at later visits. Symptom scores were not significantly related to the manner of detection or to the type of initial treatment. Potentially confounding social and personal factors did not account for the differences between patients with cancer and controls. CONCLUSION: The prevalence of anxiety and depression is not increased in long term survivors of breast cancer who are apparently free from disease and is not substantially affected by the manner in which a cancer is detected or by the treatment given. In the light of these findings it is difficult to justify large "quality adjustments" to the estimates of recurrence-free years of life saved by screening. Those who counsel patients with breast cancer should be aware that although the initial distress can be severe, meriting psychological treatment, patients do recover their normal ability to enjoy life.

Interval cancers and sensitivity in the screening centres of the UK trial of early detection of breast cancer.

The incidence rates of interval cancers following a negative breast screen in two screening centres which offered women aged 45-64 annual screening by mammography and/or clinical examination are examined. Sensitivity of screening is estimated by comparing the incidence rate of interval cancers with that expected in the absence of screening, and the results are compared with those from alternative methods of calculating sensitivity. The incidence rate of cancers diagnosed within 12 months of a negative screen by mammography plus clinical examination was reduced by 70% for women aged 45-54, and 84% for women aged 55+. There is no indication from this that sensitivity in the UK trial was substantially lower than in other studies which have achieved larger reductions in mortality.

A multivariate approach to the treatment of peripheral nerve transection injury: the role of electromagnetic field therapy.

A multivariate approach to the treatment of peripheral nerve transection injury has been used in a rat model. A pilot study (48 animals, 8 groups) examined variables associated with the method and timing of surgical repair, the arrest of wallerian degeneration, and the role of pulsing electromagnetic field therapy (PEMF) in functional recovery. A second phase (90 animals, 6 groups) then studied the timing and duration of pulsing electromagnetic field therapy as the only variable in larger groups of animals. The pilot study revealed that a vein-graft conduit did not improve functional recovery compared with standard epineurial repair. Additionally, delayed repair compared favorably with immediate repair. The use of chlorpromazine to inhibit the toxic effects of calcium influx appeared to enhance early functional recovery, and the combination of delayed nerve repair and pulsing electromagnetic field therapy seemed to consistently improve function. The second phase of the study has demonstrated (for the first time) statistical improvement in ambulation in animals treated with delayed surgical repair and prolonged pulsing electromagnetic field therapy. We postulate that future treatment of nerve transection injuries will involve a combined treatment regimen consisting of the immediate arrest of wallerian degeneration, delayed surgery, and pulsing electromagnetic field therapy.

Detection of methylated asparagine and glutamine residues in polypeptides.

A residue of gamma-N-methylasparagine (gamma-NMA) is found at position beta-72 of many phycobiliproteins. delta-N-Methylglutamine is present in some bacterial ribosomal proteins. gamma-NMA was synthesized by reacting the omega-methyl ester of aspartate with methylamine and delta-N-methylglutamine by reaction of pyroglutamate with methylamine. These derivatives and the omega-methyl esters of aspartate and glutamate were characterized by melting point, by thin-layer chromatography, by amino acid analysis, by NMR spectroscopy, and after conversion to the phenylthiohydantoin (PTH) derivative. The gamma-NMA residues in peptides from allophycocyanin, C-phycocyanin, and B-phycoerythrin were stable under the conditions of automated sequential gas-liquid phase Edman degradation. On HPLC, PTH-gamma-NMA co-eluted with PTH-serine and was accompanied by a minor component eluting just prior to dimethylphenylthiourea. Similar results were obtained on manual derivatization of synthetic gamma-NMA to prepare the PTH derivative. The PTH-delta-N-methylglutamine standard eluted near the position of dimethylphenylthiourea under the usual conditions employed for the identification of PTH-amino acid derivatives in automated protein sequencing.