Corrigendum: Modeling the volume of tissue activated in deep brain stimulation and its clinical influence: a review.

[This corrects the article DOI: 10.3389/fnhum.2024.1333183.].

Modeling the volume of tissue activated in deep brain stimulation and its clinical influence: a review.

Deep brain stimulation (DBS) is a neuromodulatory therapy that has been FDA approved for the treatment of various disorders, including but not limited to, movement disorders (e.g., Parkinson's disease and essential tremor), epilepsy, and obsessive-compulsive disorder. Computational methods for estimating the volume of tissue activated (VTA), coupled with brain imaging techniques, form the basis of models that are being generated from retrospective clinical studies for predicting DBS patient outcomes. For instance, VTA models are used to generate target-and network-based probabilistic stimulation maps that play a crucial role in predicting DBS treatment outcomes. This review defines the methods for calculation of tissue activation (or modulation) including ones that use heuristic and clinically derived estimates and more computationally involved ones that rely on finite-element methods and biophysical axon models. We define model parameters and provide a comparison of commercial, open-source, and academic simulation platforms available for integrated neuroimaging and neural activation prediction. In addition, we review clinical studies that use these modeling methods as a function of disease. By describing the tissue-activation modeling methods and highlighting their application in clinical studies, we provide the neural engineering and clinical neuromodulation communities with perspectives that may influence the adoption of modeling methods for future DBS studies.

Three new species in Russula subsection Xerampelinae supported by genealogical and phenotypic coherence.

Xerampelinae is a subsection composed of species of ectomycorrhizal fungi belonging to the hyperdiverse and cosmopolitan genus Russula (Russulales). Species of Xerampelinae are recognized by their fishy or shrimp odor, browning context, and a green reaction to iron sulfate. However, species delimitation has traditionally relied on morphology and analysis of limited molecular data. Prior taxonomic work in Xerampelinae has led to the description of as many as 59 taxa in Europe and 19 in North America. Here we provide the first multilocus phylogeny of European and North American members based on two nrDNA loci and two protein-coding genes. The resulting phylogeny supports the recognition of 17 species-rank Xerampelinae clades; however, higher species richness (~23) is suggested by a more inclusive nuclear rDNA internal transcribed spacer region ITS1-5.8S-ITS2 (ITS barcode) analysis. Phylogenetic and morphological analyses support three new species with restricted geographic distributions: R. lapponica, R. neopascua, and R. olympiana. We confirm that the European species R. subrubens is present in North America and the North American species R. serissima (previously known as R. favrei) is present in Europe. Most other Xerampelinae appear restricted to either North America or Eurasia, which indicates a high degree of regional endemism; this includes R. xerampelina, a name widely applied to North American taxa, but a species restricted to Eurasia.

Mediational pathways exploring the link between adverse childhood experiences and physical health in a transgender population.

BACKGROUND: Adverse childhood experiences (ACEs) consist of instances of abuse, neglect, or household dysfunction occurring before adulthood. Prevalence rates of ACEs are higher among specific populations, including gender minorities. In addition to ACEs, transgender individuals (TG) face many personal, social, and structural factors that have the potential to negatively impact their physical health. OBJECTIVE: This study examines exploratory mediational pathways between ACEs and two health outcomes (i.e., general health and days physically ill) in TG. Mediators include everyday discrimination, social support, gender non-affirmation, and mental distress. METHODS: Cross-sectional data from the U.S. Transgender Population Health Survey (TransPop) was used to conduct a serial/parallel mediation analysis. The TransPop survey included a total of 274 TG. RESULTS: For both outcome variables, the same three indirect pathways were significant. First, ACEs were associated with increased mental distress, which was associated with a decrease in general health and an increase in days physically ill. Second, ACEs were associated with increased discrimination, which was associated with increased mental distress, and this was associated with a decrease in general health and an increase in days physically ill. Finally, ACEs were associated with discrimination, which was associated with increased gender non-affirmation which was associated with increased mental distress, and this was associated with a decrease in general health and an increase in days physically ill. CONCLUSION: Interventions focused on reducing discrimination, gender non-affirmation, and poor mental health may be vital to improving the health of TG and to mitigating the indirect role of ACEs on TG health.

Does One Size Fit All? Variations in the DNA Barcode Gaps of Macrofungal Genera.

The nuclear ribosomal internal transcribed spacer (nrITS) region has been widely used in fungal diversity studies. Environmental metabarcoding has increased the importance of the fungal DNA barcode in documenting fungal diversity and distribution. The DNA barcode gap is seen as the difference between intra- and inter-specific pairwise distances in a DNA barcode. The current understanding of the barcode gap in macrofungi is limited, inhibiting the development of best practices in applying the nrITS region toward research on fungal diversity. This study examined the barcode gap using 5146 sequences representing 717 species of macrofungi from eleven genera, eight orders and two phyla in datasets assembled by taxonomic experts. Intra- and inter-specific pairwise distances were measured from sequence and phylogenetic data. The results demonstrate that barcode gaps are influenced by differences in intra- and inter-specific variance in pairwise distances. In terms of DNA barcode behavior, variance is greater in the ITS1 than ITS2, and variance is greater in both relative to the combined nrITS region. Due to the difference in variance, the barcode gaps in the ITS2 region are greater than in the ITS1. Additionally, the taxonomic approach of "splitting" taxa into numerous taxonomic units produces greater barcode gaps when compared to "lumping". The results show variability in the barcode gaps between fungal taxa, demonstrating a need to understand the accuracy of DNA barcoding in quantifying species richness. For taxonomic studies, variability in nrITS sequence data supports the application of multiple molecular markers to corroborate the taxonomic and systematic delineation of species.

Predictors of mood or anxiety problems among transgender individuals seeking hormone therapy.

BACKGROUND: Mental health needs of transgender individuals can be complex with individual, social, and medical factors impacting symptoms. This study examines predictors of mood or anxiety problems among transgender individuals seeking hormone therapy (HT). METHODS: A retrospective chart review was conducted at 2 clinics providing gender-affirming HT. Cross-sectional data from initial patient encounters (N = 311) were used in this study. Bivariate correlations and multiple logistic regression analyses were carried out. RESULTS: Transgender women (TW) were 2.2 times more likely to have mood or anxiety problems while transgender men (TM) were 2.6 times more likely as the number of medical comorbidities increased. For both TW and TM, White race significantly increased the likelihood of mood or anxiety problems. Neither previous nor current HT were associated with mood or anxiety problems for TW and TM. However, receiving multiple gender-affirming procedures decreased the likelihood of mood or anxiety problems for TM. CONCLUSIONS: Gender-affirming care and addressing comorbidities can be important aspects of mental health needs for transgender individuals.

The majority of transgender men and women reported 1 or more chronic health conditions. These health conditions were associated with transgender individuals being more likely to have a mood or anxiety problem. Currently receiving or previously receiving hormonal therapy was not associated with mood or anxiety problems for transgender men or women, but having received 1 or multiple gender-affirming procedures was associated with a decrease in likelihood of having a mood or anxiety problem for transgender men. White race also was associated with increased likelihood of having a mood or anxiety problem for transgender men and women. These results highlight the need for primary care physicians to take a comprehensive approach when dealing with the mental health needs of transgender patients by ensuring that general health care needs are met while receiving gender-affirming care.

Quantifying the relationship between sub-population wastewater samples and community-wide SARS-CoV-2 seroprevalence.

Robust epidemiological models relating wastewater to community disease prevalence are lacking. Assessments of SARS-CoV-2 infection rates have relied primarily on convenience sampling, which does not provide reliable estimates of community disease prevalence due to inherent biases. This study conducted serial stratified randomized samplings to estimate the prevalence of SARS-CoV-2 antibodies in 3717 participants, and obtained weekly samples of community wastewater for SARS-CoV-2 concentrations in Jefferson County, KY (USA) from August 2020 to February 2021. Using an expanded Susceptible-Infected-Recovered model, the longitudinal estimates of the disease prevalence were obtained and compared with the wastewater concentrations using regression analysis. The model analysis revealed significant temporal differences in epidemic peaks. The results showed that in some areas, the average incidence rate, based on serological sampling, was 50 % higher than the health department rate, which was based on convenience sampling. The model-estimated average prevalence rates correlated well with the wastewater (correlation = 0.63, CI (0.31,0.83)). In the regression analysis, a one copy per ml-unit increase in weekly average wastewater concentration of SARS-CoV-2 corresponded to an average increase of 1-1.3 cases of SARS-CoV-2 infection per 100,000 residents. The analysis indicates that wastewater may provide robust estimates of community spread of infection, in line with the modeled prevalence estimates obtained from stratified randomized sampling, and is therefore superior to publicly available health data.

Quantifying the relationship between sub-population wastewater samples and community-wide SARS-CoV-2 seroprevalence

BackgroundWastewater-based epidemiology is a promising approach but robust epidemiological models to relate wastewater to community prevalence are lacking. Assessments of SARS-CoV-2 infection rates have relied primarily on convenience sampling, which does not provide reliable estimates of community prevalence because of inherent biases. MethodsFrom August 2020 to February 2021, we conducted a serial stratified randomized samplings to estimate the prevalence of anti-SARS-CoV-2 antibodies in 3,717 participants, and weekly sampling of community wastewater for SARS-CoV-2 concentrations in Jefferson County, KY. With the use of a Susceptible, Infected, Recovered (SIR)-type model, we obtained longitudinal estimates of prevalence and compared these with wastewater concentration, using regression analysis. FindingsModel analysis revealed significant temporal differences in epidemic peaks; the average incidence rate based on serological sampling in some areas was up to 50% higher than health department rates based on convenience sampling. The model-estimated average prevalence rates correlated well with wastewater (correlation=0{middle dot}63). In regression analysis, a weekly unit increase in wastewater concentration of SARS-CoV-2 corresponded to an average increase of between 1-1{middle dot}3 cases of SARS-CoV-2 infection per 100K residents. InterpretationPublicly available health department incidence rates vastly underestimate true community incidence and wastewater has a high potential to provide robust estimates of community spread of infection. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAdministratively reported clinical case rates of coronavirus disease 2019 (COVID-19) infected individuals are biased due to a wide range of factors from testing access to concerns about missing low and non-symptomatic and self-tested individuals. Wastewater estimates offer an alternative to support community monitoring based on fecal shedding of the virus but are difficult to interpret when compared with the available public health data sets of infection rates. We examined all English literature until February 24, 2022, on Web of Science and PubMed with the terms ["seroprevalence" or "antibody"] AND ["COVID-19" or "SARS-CoV-2"] AND ["wastewater"]. We identified six studies. None of these studies considered randomized COVID-19 community anti-SARS-CoV-2 antibody testing paired with wastewater data. Added value of this studyThe study demonstrates how results from serial stratified randomized serological sampling of the community can be used to build a longitudinal model that can interpolate and extrapolate community levels of infection beyond specific testing dates. Such a model correlates well with wastewater concentrations indicating its utility as a surrogate for infection prevalence. The testing data used in the study were collected before wide availability of COVID-19 vaccines and are therefore unique as they are unlikely to include a significant number of false positive results. Implications of all the available evidenceThe study demonstrates that convenience sampling obtained data from health department reporting seriously underestimates community-wide prevalence of infection. In contrast, wastewater-based epidemiology may be a faster, cost-effective, and more robust method of estimating the prevalence of viral infections within specific urban areas.

Adverse Childhood Experiences and Diabetes: Testing Violence and Distress Mediational Pathways in Family Medicine Patients.

Type 2 diabetes mellitus (diabetes) is increasing in frequency and creating a significant burden on the United States healthcare system. Adverse childhood experiences (ACE) and interpersonal violence (IV) have been shown to have detrimental effects on mental and physical health. How ACE can influence IV as an adult and how this can influence the management of diabetes is not known. The purpose of the current study is to understand the relationship between violence and social determinants of health (SDoH), and its effect on patients with type 2 diabetes mellitus. A practiced-based research network (PBRN) of family medicine residency programs was utilized to collect cross-sectional data from seven family medicine residency program primary care clinics. In total, 581 participants with type 2 diabetes were recruited. A serial/parallel mediation model were analyzed. The majority of participants (58.3%) had a Hemoglobin A1c (HbA1c) that was not controlled. ACE was associated with an increase in Hurt-Insult-Threaten-Scream (HITS) scores, which in turn was positively associated with an increase in emotional burden, and finally, emotional burden decreased the likelihood that one's HbA1c was controlled (Effect = -.054, SE = .026 CI [-.115, -.013]). This indirect pathway remained significant even after controlling for several SDoH and gender. The impact of ACE persists into adulthood by altering behaviors that make adults more prone to experiencing family/partner violence. This in turn makes one more emotionally distressed about their diabetes, which influences how people manage their chronic condition. Family physicians should consider screening for both ACE and family/partner violence in those patients with poorly controlled diabetes.

Medical Comorbidities and Medication Use Among Homeless Adults Seeking Mental Health Treatment.

Little is known about the medical conditions and medication use of individuals who are homeless and have mental health problems. This study used secondary data (N = 933) from a mental health clinic serving homeless adults. Primary outcomes were the number and types of self-reported medical conditions and medications. About half (52.60%) of participants were taking one or more medications (mean = 1.67; SD = 2.30), most commonly antidepressants, antipsychotics, and anticonvulsants. Most frequently reported medical conditions were headaches/migraines, hypertension, and arthritis with a mean of 3.09 (SD = 2.74) conditions. Age and sex were significant predictors of the number of medical conditions. Age and the length of time homeless were significant predictors of the number of medications taken. Results suggest that those who are older and have been homeless longer appear to be increased risk for health problems and may need more medications to manage these conditions.

Pair-bonding, fatherhood, and the role of testosterone: A meta-analytic review.

Males of many species must allocate limited energy budgets between mating and parenting effort. The Challenge Hypothesis provides a framework for understanding these life-history trade-offs via the disparate roles of testosterone (T) in aggression, sexual behavior, and parenting. It predicts that males pursuing mating opportunities have higher T than males pursuing paternal strategies, and in humans, many studies indeed report that men who are fathers and/or pair-bonded have lower T than childless and/or unpaired men. However, the magnitude of these effects, and the influence of methodological variation on effect sizes, have not been quantitatively assessed. We meta-analyzed 114 effects from 66 published and unpublished studies covering four predictions inspired by the Challenge Hypothesis. We confirm that pair-bonded men have lower T than single men, and fathers have lower T than childless men. Furthermore, men more oriented toward pair-bonding or offspring investment had lower T. We discuss the practical meaningfulness of the effect sizes we estimate in relation to known factors (e.g., aging, geographic population) that influence men's T concentrations.

The train the trainer model for the propagation of resuscitation knowledge in limited resource settings: A systematic review.

BACKGROUND: The Train the Trainer (TTT) model is increasingly used in limited resource settings as a mechanism to disseminate resuscitation knowledge and skills among providers. Anecdotally, however, many resuscitation programs that use this model fail to achieve sustainability. OBJECTIVE: We aim to systematically review the literature to describe the evidence for the TTT method of knowledge dissemination for resuscitation courses in limited resource settings. METHODS: We conducted a systematic review of the literature in accordance with PRISMA guidelines of the PubMed, Cochrane Library, MEDLARS online (MEDLINE), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. RESULTS: Eleven manuscripts met inclusion criteria, the majority (7/11) focused on neonatal resuscitation. We found strong evidence for the TTT model for imparting knowledge and skills on providers, however, little evidence exists for the impact of these programs on patient outcomes or long term sustainability. Facilitators associated with successful programming include the use of language and resource appropriate materials, support from the Ministry of Health of the country, and economic support for supplies and salaries. CONCLUSION: While the TTT model of programming for the dissemination of resuscitation education is promising, further research is necessary especially relating to sustainability and impact on patient outcomes. Familiarity with the local environment, language, culture, resources and economic realities prior to the initiation of programming is key to success.

Effect of repeated exposure to AQUI-S® on the viability and growth of Neoparamoeba perurans.

There have been recent efforts amongst immunologists to develop approaches for following individual fish during challenges with viral and bacterial pathogens. This study contributes to assessing the feasibility of using such approaches to study amoebic gill disease (AGD). Neoparamoeba perurans, agent of AGD, has been responsible for widespread economic and fish loss in salmonid aquaculture. With the emergence of AGD in Europe, research into infection dynamics and host response has increased. This study investigated the effect of repeat exposure to anaesthesia, a necessary requirement when following disease progression in individual fish, on N. perurans. In vitro cultures of N. perurans were exposed every 4 days over a 28-day period to AQUI-S® (isoeugenol), a popular anaesthetic choice for AGD challenges, at a concentration and duration required to sedate post-smolt salmonids. Population growth was measured by sequential counts of amoeba over the period, while viability of non-attached amoeba in the culture was assessed with a vital stain. AQUI-S® was found to be a suitable choice for in vivo ectoparasitic challenges with N. perurans during which repetitive anaesthesia is required for analysis of disease progression.

Atmospheric transport of trace elements and nutrients to the oceans.

This paper reviews atmospheric inputs of trace elements and nutrients to the oceans in the context of the GEOTRACES programme and provides new data from two Atlantic GEOTRACES cruises. We consider the deposition of nitrogen to the oceans, which is now dominated by anthropogenic emissions, the deposition of mineral dust and related trace elements, and the deposition of other trace elements which have a mixture of anthropogenic and dust sources. We then consider the solubility (as a surrogate for bioavailability) of the various elements. We consider briefly the sources, atmospheric transport and transformations of these elements and how this results in strong spatial deposition gradients. Solubility of the trace elements also varies systematically between elements, reflecting their sources and cycling, and for some trace elements there are also systematic gradients in solubility related to dust loading. Together, these effects create strong spatial gradients in the inputs of bioavailable trace elements to the oceans, and we are only just beginning to understand how these affect ocean biogeochemistry.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.

The Curse of Curves: Sex Differences in the Associations Between Body Shape and Pain Expression.

This study examines the associations between objective and subjective measurements and impressions of body shape and cold pressor pain reporting in healthy adults. On the basis of sexual selection theory (SST), we hypothesized that body characteristics that are universally preferred by the opposite sex-specifically, lower waist-to-hip ratios (WHR) in women and higher shoulder-to-hip ratios (SHR) in men-and characteristics (e.g., proportion of body fat in women) that infer attractiveness differently across cultures will correspond to higher experimental pain reporting in women and lower pain reporting in males. A convenience sample of young adults (n = 96, 58 females, 18-24 years; mean age = 19.4) was measured for body mass index (BMI), WHR, SHR, and subjective body impressions (SBI), along with cold pressor pain reporting. The findings showed that BMI was positively associated with WHR and less-positive SBI in both sexes. Consistent with SST, however, only BMI and WHR predicted variability in pain expression in women, whereas only SHR predicted variability in men. Subjective body impressions were positively associated with SHR among males and unrelated to WHR among females, yet only females showed a positive association between SBI and higher pain reporting. The findings suggest that sexually selected physical characteristics (WHR and SHR) and culturally influenced somatic (BMI) and psychological (SBI) indicators of attractiveness correspond with variability in pain reporting, potentially reflecting the general tendency for people to express clusters of sexually selected and culturally influenced traits that may include differential pain perception.

Determination of total and non-water soluble iodine in atmospheric aerosols by thermal extraction and spectrometric detection (TESI).

Iodine has recently been of interest in atmospheric chemistry due to its role in tropospheric ozone depletion, modification of the HO/HO(2) ratio and aerosol nucleation. Gas-phase iodine chemistry is tightly coupled to the aerosol phase through heterogeneous reactions, which are dependent on iodine concentrations and speciation in the aerosol. To date, the only method available for total iodine determination in aerosols is collection on filters by impaction and quantification by neutron activation analysis (NAA). NAA is not widely available to all working groups and is costly to commission. Here, we present a method to determine total iodine concentrations in aerosol impact filter samples by combustion of filter sub-samples (approximately 5 cm(2)) at 1,000 degrees C, trapping in deionised water and quantification by UV/Vis spectroscopy. Both quartz and cellulose filters were analysed from four separate sampling campaigns. The method proved to be sensitive (3sigma = 6 ng absolute iodine approximately 3 pmol m(-3)) precise (RSD approximately 5%) and accurate, as determined by external and standard addition calibrations. Total iodine concentrations ranged from 10 pmol m(-3) over the Southern Ocean to 100 pmol m(-3) over the tropical Atlantic, in agreement with previous estimates. The soluble iodine concentration (extracted with water and measured by ICP-MS) was then subtracted from the total iodine to yield non-water-soluble iodine (NSI). The NSI fraction ranged from 20% to 53% of total iodine, and thus can be significant in some cases.

Insulin self-association and the relationship to pharmacokinetics and pharmacodynamics.

The treatment of type 1 diabetes requires multiple, daily injections of insulin. While many improvements involving formulation adjustments have been made in an attempt to optimize therapy, clinical experience indicates that the commercially available insulin preparations used for treatment have significant limitations. One principal deficiency relates to poor simulation of the physiological insulin secretion pattern, making achieving normalization of blood glucose concentrations difficult. Endogenous insulin secretion in nondiabetic subjects is characterized by a pulsatile profile that displays multiple, meal-stimulated phases and low basal concentrations between meals and overnight. Optimal diabetes therapy, therefore, requires insulin preparations that display a rapid onset of action with corresponding rapid clearance to provide for meal ingestion as well as preparations that can maintain a sustained, peakless profile for basal requirements. Recent efforts in pharmaceutical research have used the concept of rational-based design of the insulin molecule in an attempt to produce preparations that display more ideal pharmacological profiles. Using detailed structural information obtained from X-ray crystallographic studies to guide design strategies and exploit the nonrestrictive synthetic capabilities of recombinant DNA technology, researchers have prepared a number of insulin analogs that display a reduced propensity towards self-association. Clinical evaluations have shown that these so called "monomeric" analogs better mimic the meal-stimulated pharmacokinetics of insulin secretion observed in nondiabetics. Two monomeric insulin analog preparations have successfully obtained regulatory approval and are now commercially available. Efforts to produce optimized basal-acting insulin analogs have lagged behind. While some of these analogs have been engineered using recombinant DNA technology, design strategies in many cases exploit physicochemical properties of insulin other than self-association. One basal insulin analog has recently received regulatory approval. This paper reviews insulin self-association and its relationship to pharmacokinetics and pharmacodynamics. Particular emphasis is placed on the approaches used to manipulate self-assembly resulting in meal-time insulin analogs that display optimal pharmacological properties. Other design strategies used to develop improved basal insulin preparations are also considered.

Insulin autoantibodies: more specific than proinsulin autoantibodies for prediction of type 1 diabetes.

Proinsulin autoantibodies (PAA) are a potential alternative to insulin autoantibodies (IAA) for the prediction of type 1 diabetes. We measured the prevalence of PAA and IAA in 179 patients with newly diagnosed type 1 diabetes and 1028 schoolchildren, and compared the potential of these antibodies for disease prediction. Antibodies were measured using a novel microassay in which screening for binding of radio-labelled antigen was followed by competitive displacement. Thresholds for both antigen binding and competitive displacement were selected so that equivalent numbers of patients with type 1 diabetes were identified by the proinsulin and insulin antibody assays. Similar numbers of schoolchildren were found to have insulin and proinsulin binding above the screening threshold but, after competitive displacement, the prevalence of PAA (3.7%) was more than twice that of IAA (1.4%) with 66% sensitivity. Both PAA and IAA were present in 113 (63%) of patients, as against 0.8% of schoolchildren, implying that individuals with both antibodies are at particularly high risk of disease. The majority of samples with IAA or PAA were displaced with both insulin and proinsulin, suggesting that the main epitopes recognized by these antibodies are on the insulin molecule. We conclude that IAA are more specific than PAA for the prediction of type 1 diabetes.

Differences in the cellular processing of AspB10 human insulin compared with human insulin and LysB28ProB29 human insulin.

Cellular metabolism studies were performed comparing human insulin with two rapid-acting analogs, LysB28ProB29 insulin (LysPro) and AspB10 insulin (B10-Asp). B10-Asp bound to isolated hepatocytes at 37 degrees C to a greater extent than LysPro or native insulin, which were equivalent. The rate of degradation was similar for the three materials, resulting in a significant reduction in the degraded/bound ratio for the B10 analog. The processing of membrane-bound material was examined by incubating cells with hormone at 4 degrees C, removing unbound insulin, and incubating the cells at 37 degrees C. Again, binding was greater for B10-Asp versus LysPro or native insulin, with a reduction in the degraded/bound ratio. Hormone internalization and processing was examined by an acid wash of cells incubated with 125I(A14)-labeled hormone to remove surface-bound materials. The processing rate was slower for B10-Asp versus LysPro or native insulin. Cell extraction and examination on molecular-sieve chromatography confirmed that B10-Asp was processed at a slower rate than either LysPro or native insulin. Intact B10-Asp was found in the cell after 4 hours, whereas all native insulin and LysPro were degraded by 90 to 120 minutes. B10-Asp also caused a greater incorporation of thymidine into DNA in cultured cells than LysPro or native insulin, which were similar. These data show that the cellular processing of LysPro is essentially identical to that of native insulin. However, B10-Asp has markedly different properties and is processed much more slowly. The prolonged cell residence time of B10-Asp could contribute to its greater effects on cell growth and mitogenesis.

Sensitive RIA for the specific determination of insulin lispro.

Insulin lispro is an insulin analog in which the primary sequence has been altered by the inversion of amino acids B28 and B29. To date, it has not been possible to specifically measure insulin lispro in the presence of endogenous insulin because of the high degree of homology between these peptides. However, the specific determination of insulin lispro offers advantages over quantifying total concentrations of immunoreactive insulin. We therefore immunized guinea pigs and screened for antibodies with increased affinity and selectivity for insulin lispro. We prepared a monospecific antiserum by a novel immunoadsorption strategy using despentapeptide insulin. The antiserum was used to develop a competitive RIA for insulin lispro. The RIA has a low limit of quantification (17.2 pmol/L); has no interference from insulin, proinsulin, or C-peptide; and has interassay CVs of 2.6-13.4%. The new RIA is useful for measuring serum concentrations of insulin lispro.