Spike Spectra for Recurrences.

In recurrence analysis, the τ-recurrence rate encodes the periods of the cycles of the underlying high-dimensional time series. It, thus, plays a similar role to the autocorrelation for scalar time-series in encoding temporal correlations. However, its Fourier decomposition does not have a clean interpretation. Thus, there is no satisfactory analogue to the power spectrum in recurrence analysis. We introduce a novel method to decompose the τ-recurrence rate using an over-complete basis of Dirac combs together with sparsity regularization. We show that this decomposition, the inter-spike spectrum, naturally provides an analogue to the power spectrum for recurrence analysis in the sense that it reveals the dominant periodicities of the underlying time series. We show that the inter-spike spectrum correctly identifies patterns and transitions in the underlying system in a wide variety of examples and is robust to measurement noise.

Thyroid nodules in xeroderma pigmentosum patients: a feature of premature aging.

PURPOSE: Xeroderma pigmentosum (XP) is an autosomal recessive disease with defective DNA repair, a markedly increased risk of skin cancer, and premature aging. Reports from North Africa have described thyroid nodules in XP patients, but thyroid nodule prevalence has never been determined in XP patients enrolled in our natural history study at the National Institutes of Health (NIH). METHODS: We performed thyroid ultrasound examinations on all 29 XP patients examined from 2011 to 2019 and assessed nodule malignancy using the Thyroid Imaging Reporting and Data System. Thyroid nodule prevalence was also obtained from comparison cohorts. DNA sequencing was performed on thyroid tissue from XP patients who had surgery for thyroid cancer. RESULTS: Thyroid nodules were identified in 18/29 XP patients (62%). The median age of patients with thyroid nodules in our XP cohort (20 years) was younger than that of three comparison groups: 36 years (California study-208 subjects), 48 years (Korean study-24,757 subjects), and 52 years (NIH-682 research subjects). Multiple (2-4) thyroid nodules were found in 12/18 (67%) of the patients with nodules. Autopsy examination revealed follicular adenomas in 4/8 (50%) additional XP patients. DNA sequencing revealed rare mutations in two other XP patients with papillary thyroid cancer. CONCLUSIONS: XP patients have an increased incidence of thyroid nodules at an early age in comparison to the general population. These finding confirm another premature aging feature of XP.

Motor execution reduces EEG signals complexity: Recurrence quantification analysis study.

The development of new approaches to detect motor-related brain activity is key in many aspects of science, especially in brain-computer interface applications. Even though some well-known features of motor-related electroencephalograms have been revealed using traditionally applied methods, they still lack a robust classification of motor-related patterns. Here, we introduce new features of motor-related brain activity and uncover hidden mechanisms of the underlying neuronal dynamics by considering event-related desynchronization (ERD) of µ-rhythm in the sensorimotor cortex, i.e., tracking the decrease of the power spectral density in the corresponding frequency band. We hypothesize that motor-related ERD is associated with the suppression of random fluctuations of µ-band neuronal activity. This is due to the lowering of the number of active neuronal populations involved in the corresponding oscillation mode. In this case, we expect more regular dynamics and a decrease in complexity of the EEG signal recorded over the sensorimotor cortex. In order to support this, we apply measures of signal complexity by means of recurrence quantification analysis (RQA). In particular, we demonstrate that certain RQA quantifiers are very useful to detect the moment of movement onset and, therefore, are able to classify the laterality of executed movements.

Recurrence threshold selection for obtaining robust recurrence characteristics in different embedding dimensions.

The appropriate selection of recurrence thresholds is a key problem in applications of recurrence quantification analysis and related methods across disciplines. Here, we discuss the distribution of pairwise distances between state vectors in the studied system's state space reconstructed by means of time-delay embedding as the key characteristic that should guide the corresponding choice for obtaining an adequate resolution of a recurrence plot. Specifically, we present an empirical description of the distance distribution, focusing on characteristic changes of its shape with increasing embedding dimension. Our results suggest that selecting the recurrence threshold according to a fixed percentile of this distribution reduces the dependence of recurrence characteristics on the embedding dimension in comparison with other commonly used threshold selection methods. Numerical investigations on some paradigmatic model systems with time-dependent parameters support these empirical findings.

Impact of bispectral index for monitoring propofol remifentanil anaesthesia. A randomised clinical trial.

BACKGROUND: Previous research has shown that the use of the bispectral index (BIS) monitor to measure the depth of anaesthesia reduces the amount of anaesthetics administered and the recovery time from general anaesthesia. The effect of BIS on recovery from anaesthesia and consumption of anaesthetics in a paediatric population receiving total intravenous anaesthesia (TIVA) with propofol and remifentanil has not been studied. METHODS: A single-blind, single-centre clinical trial. One hundred fifty-seven patients were enrolled. They were scheduled for ear, nose, and throat surgery and stratified according to age groups (1-3 years, 4-11 years, 12-17 years, 18-65 years) and type of operation, yielding a total of nine subgroups. Patients were randomly allocated to receive either a TIVA with propofol and remifentanil according to conventional clinical practice (control) or guided by BIS. Normalised propofol (µg/kg/min) and remifentanil (µg/kg/min) consumption and time to extubation (s) were the outcome measures. RESULTS: Children aged 1-3 years in the BIS group had a longer time to extubation compared with controls (P: 0.04). Patients aged 12-17 years in the BIS group received higher maintenance infusion rates of propofol compared with controls (P = 0.02). No significant difference for the outcome variables was evidenced in the other age groups. CONCLUSION: BIS monitoring for guidance of propofol-remifentanil anaesthesia does not result in reduced consumption of anaesthetics and does not reduce time to extubation in adult and children compared with conventional practice.

Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair.

While investigating the novel anticancer drug ecteinascidin 743 (Et743), a natural marine product isolated from the Caribbean sea squirt, we discovered a new cell-killing mechanism mediated by DNA nucleotide excision repair (NER). A cancer cell line selected for resistance to Et743 had chromosome alterations in a region that included the gene implicated in the hereditary disease xeroderma pigmentosum (XPG, also known as Ercc5). Complementation with wild-type XPG restored the drug sensitivity. Xeroderma pigmentosum cells deficient in the NER genes XPG, XPA, XPD or XPF were resistant to Et743, and sensitivity was restored by complementation with wild-type genes. Moreover, studies of cells deficient in XPC or in the genes implicated in Cockayne syndrome (CSA and CSB) indicated that the drug sensitivity is specifically dependent on the transcription-coupled pathway of NER. We found that Et743 interacts with the transcription-coupled NER machinery to induce lethal DNA strand breaks.

Relationship of household food insecurity to anaemia in children aged 6-59 months among families in rural Indonesia.

BACKGROUND: Anaemia is a significant global public health problem in developing countries with adverse health effects on young children. Household food insecurity, which reflects a household's access, availability and utilisation of food, has not been well characterised in relation to anaemia in children. OBJECTIVE: To examine the relationship of household food insecurity with anaemia (Hb <11 g/dl) in children. METHODS: In a cross-sectional study of 4940 rural households participating in the Indonesian Nutrition Surveillance System, household food insecurity was measured using a modified 9-item food security questionnaire and related to anaemia in children aged 6-59 months. RESULTS: The proportion of households with an anaemic child was 56·6%. In households with and without anaemic children, the mean (SD) food insecurity score was 1·82 (1·72) vs 1·55 (1·54) (p<0·0001), respectively. In a multivariate logistic regression model, food insecurity score was related to anaemia in children (odds ratio 0·77, 95% confidence interval 0·63-0·95, p=0·01) when the highest quintile of food insecurity score was compared with the lowest quintile, adjusting for potential confounders. CONCLUSION: A higher household food insecurity score is associated with greater prevalence of anaemia in children in rural families in Indonesia.

Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development.

The effects of DNA repair and transcription gene abnormalities in human pre-natal life have never been studied. Trichothiodystrophy (TTD) is a rare (affected frequency of 10(-6)) recessive disorder caused by mutations in genes involved in nucleotide excision repair (NER) pathway and in transcription. Based on our novel clinical observations, we conducted a genetic epidemiologic study to investigate gestational outcomes associated with TTD. We compared pregnancies resulting in TTD-affected offspring (n = 24) with respect to abnormalities during their antenatal and neonatal periods to pregnancies resulting in their unaffected siblings (n = 18), accounting for correlation, and to population reference values. Significantly higher incidence of several severe gestational complications was noted in TTD-affected pregnancies. Small for gestational age (SGA) <10th percentile [Relative risk (RR ) = 9.3, 95% CI = 1.4-60.5, p = 0.02], SGA <3rd percentile (RR = 7.2, 95% CI = 1.1-48.1, p = 0.04), and neonatal intensive care unit (NICU) hospitalization (RR = 6.4, 95% CI = 1.4-29.5, p = 0.02) occurred more frequently among TTD-affected neonates compared with their unaffected siblings. Compared with reference values from general obstetrical population, pregnancies that resulted in TTD-affected infants were significantly more likely to be complicated by hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (RR = 35.7, 95% CI = 7.6-92.5, p = 0.0002), elevated mid-trimester maternal serum human chorionic gonadotropin (hCG) levels (RR = 14.3, 95% CI = 7.0-16.6, p < 0.0001), SGA <3rd percentile (RR = 13.9, 95% CI = 7.4-21.1, p < 0.0001), pre-term delivery (<32 weeks) (RR = 12.0, 95% CI = 4.9-21.6, p < 0.0001), pre-eclampsia (RR = 4.0, 95% CI = 1.6-7.4, p = 0.006), and decreased fetal movement (RR = 3.3, 95% CI = 1.6-5.2, p = 0.0018). Abnormal placental development is an underlying mechanism that may explain the constellation of observed complications in our study. Thus, we hypothesize that TTD DNA repair and transcription genes play an important role in normal human placental development.

Delivery of carboplatin by carbon-based nanocontainers mediates increased cancer cell death.

Since the activity of several conventional anticancer drugs is restricted by resistance mechanisms and dose-limiting side-effects, the design of nanocarriers seems to be an efficient and promising approach for drug delivery. Their chemical and mechanical stability and their possible multifunctionality render tubular nanomaterials, such as carbon nanotubes (CNTs) and carbon nanofibres (CNFs), promising delivery agents for anticancer drugs. The goal of the present study was to investigate CNTs and CNFs in order to deliver carboplatin in vitro. No significant intrinsic toxicity of unloaded materials was found, confirming their biocompatibility. Carboplatin was loaded onto CNTs and CNFs, revealing a loading yield of 0.20 mg (CNT-CP) and 0.13 mg (CNF-CP) platinum per milligram of material. The platinum release depended on the carrier material. Whereas CNF-CP marginally released the drug, CNT-CP functioned as a drug depot, constantly releasing up to 68% within 14 days. The cytotoxicity of CNT-CP and CNF-CP in urological tumour cell lines was dependent on the drug release. CNT-CP was identified to be more effective than CNF-CP concerning the impairment of proliferation and clonogenic survival of tumour cells. Moreover, carboplatin, which was delivered by CNT-CP, exhibited a higher anticancer activity than free carboplatin.

Geographic access to buprenorphine prescribers for patients who use public transit.

OBJECTIVE: Urban Medicaid enrollees with opioid use disorder often rely on public transit to reach buprenorphine prescribers. Research has not shown whether public transit provides this population with adequate geographic access to buprenorphine prescribers. We examined travel times to buprenorphine prescribers by car and public transit in urban areas, and determined whether car-based Medicaid regulatory standards produce their intended geographic coverage. METHODS: We obtained data for this study from the Substance Abuse and Mental Health Services Administration's Buprenorphine Practitioner Locator, Microsoft Bing Maps, and the American Community Survey. We examined four urban counties at the centers of the metropolitan statistical areas with the highest 2017 accidental drug poisoning death rates: Kanawha, WV; Montgomery, OH; Philadelphia, PA; and St. Louis City, MO. These counties comprised 696 census tracts representing 1,038,564 households. We calculated travel times from each census tract center to the nearest buprenorphine prescribers by car and public transit, and compared that to 30-min regulatory standards and by whether census tracts had below median levels of car access. We calculated Global Moran's I statistics to determine whether spatial clustering was present among census tracts with limited access to buprenorphine prescribers. RESULTS: Households in all but two census tracts could access a buprenorphine prescriber within 30 min by car. However, households in 12.1% (84) of census tracts could not do so by public transit. The correlation between car- and public transit-based travel times to the nearest buprenorphine prescriber was 0.11 (95% CI = 0.07-0.22). More than 15% (47,918) of households in the two less densely populated counties could not travel to the nearest prescriber in 30 min and resided in census tracts where access to cars was relatively low. There was no evidence of spatial clustering among census tracts with public transit travel times exceeding 30 min, or among census tracts with public transit travel times exceeding 30 min and below median values of access to cars. CONCLUSIONS: Geographic access to buprenorphine prescribers is overestimated by regulatory standards that apply car-based travel time estimates, which are a weak proxy for public transit-based travel times. Since geographic areas with limited access to buprenorphine prescribers do not tend to cluster near one another, individually targeted interventions may be necessary to improve buprenorphine access and utilization.

Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations.

Trichothiodystrophy (TTD) is a rare, autosomal recessive disease, characterised by brittle, sulfur deficient hair and multisystem abnormalities. A systematic literature review identified 112 patients ranging from 12 weeks to 47 years of age (median 6 years). In addition to hair abnormalities, common features reported were developmental delay/intellectual impairment (86%), short stature (73%), ichthyosis (65%), abnormal characteristics at birth (55%), ocular abnormalities (51%), infections (46%), photosensitivity (42%), maternal pregnancy complications (28%) and defective DNA repair (37%). There was high mortality, with 19 deaths under the age of 10 years (13 infection related), which is 20-fold higher compared to the US population. The spectrum of clinical features varied from mild disease with only hair involvement to severe disease with profound developmental defects, recurrent infections and a high mortality at a young age. Abnormal characteristics at birth and pregnancy complications, unrecognised but common features of TTD, suggest a role for DNA repair genes in normal fetal development.

Expression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft-tissue sarcoma.

Self-renewal is considered as a common property of stem cells. Dysregulation of stem cell self-renewal is likely a requirement for the development of cancer. Hiwi, the human Piwi gene, encodes a protein responsible for stem cell self-renewal. In this study, we investigated the expression of Hiwi at the RNA level by real-time quantitative PCR in 65 primary soft-tissue sarcomas (STS) and ascertained its impact on prognosis for STS patients. In a multivariate Cox's proportional hazards regression model, we found that an increased expression of Hiwi mRNA is a significant negative prognostic factor for patients with STS (P=0.017; relative risk 4.6, 95% confidence interval (CI) 1.3-16.1) compared to medium expression of Hiwi transcript. However, a low expression of Hiwi transcript is correlated with a 2.4-fold (CI 0.7-8.0) increased risk, but this effect was not significant (P=0.17). Altogether, high-level expression of Hiwi mRNA identifies STS patients at high risk of tumour-related death. This is the first report showing a correlation between expression of a gene involved in stem cell self-renewal and prognosis of cancer patients.

Impaired interferon production and natural killer cell activation in patients with the skin cancer-prone disorder, xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder with sun sensitivity, markedly increased skin cancer susceptibility, and defective DNA repair without consistently identified symptoms of immune deficiency. We examined natural killer (NK) cell activity and interferon production in peripheral blood lymphocytes (PBL) of eight XP patients who had multiple primary skin cancers. The XP patients had normal numbers of T cells and NK cells, as well as normal lymphokine-activated killer cell activity and normal tumor necrosis factor-alpha production. Unstimulated NK cell function was 40% of normal controls in five XP patients, but was normal in three other XP patients. However, PBL from all the XP patients tested showed no enhancement of NK activity by the interferon inducer, polyinosinic acid:polycytidilic acid (polyIC) but enhancement by interferon-alpha was normal, suggesting an impairment in interferon production. Parallel studies in non-XP skin cancer patients revealed that both unstimulated and polyIC-enhanced NK activity were normal. Further investigation using PBL from XP patients revealed that the production of interferon-gamma after stimulation with interferon inducers (polyIC, interleukin 2, or K562 tumor cells) was 13-43% of normals. These data indicate that XP lymphocytes have a defect in production of interferons and suggest that defective interferon production, as well as DNA repair defects, may play an important role in the susceptibility of XP patients to skin cancer.

Abnormal ultraviolet mutagenic spectrum in plasmid DNA replicated in cultured fibroblasts from a patient with the skin cancer-prone disease, xeroderma pigmentosum.

A shuttle vector plasmid, pZ189, was utilized to assess the types of mutations that cells from a patient with xeroderma pigmentosum, complementation group D, introduce into ultraviolet (UV) damaged, replicating DNA. Patients with xeroderma pigmentosum have clinical and cellular UV hypersensitivity, increased frequency of sun-induced skin cancer, and deficient DNA repair. In comparison to UV-treated pZ189 replicated in DNA repair-proficient cells, there were fewer surviving plasmids, a higher frequency of plasmids with mutations, fewer plasmids with two or more mutations in the marker gene, and a new mutagenic hotspot. The major type of base substitution mutation was the G:C to A:T transition with both cell lines. These results, together with similar findings published earlier with cells from a xeroderma pigmentosum patient in complementation group A, suggest that isolated G:C to A:T somatic mutations may be particularly important in generation of human skin cancer by UV radiation.

Retinoid protection against x-ray-induced chromatid damage in human peripheral blood lymphocytes.

Oral administration of isotretinoin (13-cis retinoic acid) was shown previously (Kraemer, K. H., J. J. DiGiovanna, A. N. Moshell, R. E. Tarone, and G. L. Peck. 1988. N. Engl. J. Med. 318:1633-1637) to reduce the frequency of skin cancers in xeroderma pigmentosum (XP) patients. The mechanism of protection was unclear. In the present study, x-ray-induced chromatid damage in PHA-stimulated blood lymphocytes from five XP patients receiving isotretinoin was approximately half that in blood samples from the same patients before or subsequent to treatment. The x-ray-induced chromatid damage in blood lymphocytes from a normal control was reduced significantly by cocultivation with blood or plasma from an XP patient receiving isotretinoin or by addition of 10(-6) M isotretinoin to cultures 1 h before x-irradiation. A similar reduction in x-ray-induced chromatid damage was reported previously by adding to the culture medium, mannitol, a scavenger of the free hydroxyl radical, or catalase, which decomposes hydrogen peroxide; both of these products are generated during ionizing radiation. The present observations suggest that isotretinoin acts as a scavenger of such radiation products, thereby providing protection against x-ray-induced chromatid damage.

Carrier detection in xeroderma pigmentosum.

We were able to detect clinically normal carriers of xeroderma pigmentosum (XP) genes with coded samples of either peripheral blood lymphocytes or skin fibroblasts, using a cytogenetic assay shown previously to detect individuals with cancer-prone genetic disorders. Metaphase cells of phytohemagglutinin-stimulated T-lymphocytes from eight individuals who are obligate heterozygotes for XP were compared with those from nine normal controls at 1.3, 2.3, and 3.3 h after x-irradiation (58 R) during the G2 phase of the cell cycle. Lymphocytes from the XP heterozygotes had twofold higher frequencies of chromatid breaks or chromatid gaps than normal (P less than 10(-5)) when fixed at 2.3 or 3.3 h after irradiation. Lymphocytes from six XP homozygotes had frequencies of breaks and gaps threefold higher than normal. Skin fibroblasts from an additional obligate XP heterozygote, when fixed approximately 2 h after x-irradiation (68 R), had a twofold higher frequency of chromatid breaks and a fourfold higher frequency of gaps than fibroblasts from a normal control. This frequency of aberrations in cells from the XP heterozygote was approximately half that observed in the XP homozygote. The elevated frequencies of chromatid breaks and gaps after G2 phase x-irradiation may provide the basis of a test for identifying carriers of the XP gene(s) within known XP families.

Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship.

Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least eight overlapping phenotypes. The clinical features of these patients have some similarities but also have marked differences. NER is involved in protection against sunlight-induced DNA damage. While XP patients have 1000-fold increase in susceptibility to skin cancer, TTD and CS patients have normal skin cancer risk. Several of the genes involved in NER also affect somatic growth and development. Some patients have short stature and immature sexual development. TTD patients have sulfur deficient brittle hair. Progressive sensorineural deafness is an early feature of XP and CS. Many of these clinical diseases are associated with developmental delay and progressive neurological degeneration. The main neuropathology of XP is a primary neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the brain. These complex neurological abnormalities are not related to sunlight exposure but may be caused by developmental defects as well as faulty repair of DNA damage to neuronal cells induced by oxidative metabolism or other endogenous processes.

UV light-induced cyclobutane pyrimidine dimers are mutagenic in mammalian cells.

We used a simian virus 40-based shuttle vector plasmid, pZ189, to determine the role of pyrimidine cyclobutane dimers in UV light-induced mutagenesis in monkey cells. The vector DNA was UV irradiated and then introduced into monkey cells by transfection. After replication, vector DNA was recovered from the cells and tested for mutations in its supF suppressor tRNA marker gene by transformation of Escherichia coli carrying a nonsense mutation in the beta-galactosidase gene. When the irradiated vector was treated with E. coli photolyase prior to transfection, pyrimidine cyclobutane dimers were removed selectively. Removal of approximately 90% of the pyrimidine cyclobutane dimers increased the biological activity of the vector by 75% and reduced its mutation frequency by 80%. Sequence analysis of 72 mutants recovered indicated that there were significantly fewer tandem double-base changes and G X C----A X T transitions (particularly at CC sites) after photoreactivation of the DNA. UV-induced photoproducts remained (although at greatly reduced levels) at all pyr-pyr sites after photoreactivation, but there was a relative increase in photoproducts at CC and TC sites and a relative decrease at TT and CT sites, presumably due to a persistence of (6-4) photoproducts at some CC and TC sites. These observations are consistent with the fact that mutations were found after photoreactivation at many sites at which only cyclobutane dimers would be expected to occur. From these results we conclude that UV-induced pyrimidine cyclobutane dimers are mutagenic in DNA replicated in monkey cells.