The late-presenting HIV-infected patient 30 years after the introduction of HIV testing: spectrum of opportunistic diseases and missed opportunities for early diagnosis.

OBJECTIVES: The aim of the study was to describe the characteristics of HIV-infected late presenters, opportunistic diseases at diagnosis and missed opportunities to diagnose HIV infection earlier. METHODS: In a retrospective cohort study, we reviewed the medical records of all adults with newly diagnosed HIV infection admitted to the Department of Infectious Diseases of the Vivantes Auguste-Viktoria Hospital, Berlin, Germany. RESULTS: In the 5-year period from 2009 to 2013, 270 late presenters were identified. The most common AIDS-defining conditions were oesophageal candidiasis (n = 136; 51%), wasting syndrome (n = 106; 40%) and pneumocystis pneumonia (n = 91; 34%). Fifty-five patients (21%) had presented with at least one HIV indicator condition on prior contact with health care services without being offered testing for HIV. Female patients and heterosexual men [not men who have sex with men ('non-MSM')] had a significantly higher chance of being among patients previously presenting with indicator conditions and not being tested [odds ratio (OR) 4.7; 95% confidence interval (CI) 2.2-10.0; P < 0.001; and OR 2.4; 95% CI 1.2-5.1; P < 0.01, respectively]. The most commonly missed indicator conditions were leucocytopenia (n = 13; 24%), thrombocytopenia (n = 12; 22%), oral candidiasis (n = 9; 16%), unexplained weight loss (n = 7; 13%), herpes zoster (n = 5; 9%) and cervical dysplasia/cancer (n = 4; 20% of women). The median time between presentation with an indicator condition and the diagnosis of HIV infection was 158.5 days [interquartile range (IQR) 40-572 days]. Patients with oral candidiasis and unexplained weight loss had the shortest time between the "missed opportunity" and the diagnosis of HIV infection. Fifty-five hospital admissions with a total cost of over EUR 500 000 and - most importantly - six in-hospital deaths might have been prevented if HIV testing had been performed in patients with documented indicator conditions. CONCLUSIONS: Indicator conditions are still missed by clinicians. Women and 'non-MSM' are at highest risk of presenting with an indicator condition but not being tested for HIV infection.

In vitro to in vivo extrapolation from three-dimensional hiPSC-derived cardiac microtissues and physiologically based pharmacokinetic modeling to inform next-generation arrhythmia risk assessment.

Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. In vitro human pluripotent stem cell-based new approach methodologies have been increasingly proposed and employed as alternatives to existing in vitro and in vivo models that do not accurately recapitulate human cardiac electrophysiology or cardiotoxicity risk. In this study, we expanded the capacity of our previously established three-dimensional human cardiac microtissue model to perform quantitative risk assessment by combining it with a physiologically based pharmacokinetic model, allowing a direct comparison of potentially harmful concentrations predicted in vitro to in vivo therapeutic levels. This approach enabled the measurement of concentration responses and margins of exposure for two physiologically relevant metrics of proarrhythmic risk (ie, action potential duration and triangulation assessed by optical mapping) across concentrations spanning three orders of magnitude. The combination of both metrics enabled accurate proarrhythmic risk assessment of four compounds with a range of known proarrhythmic risk profiles (ie, quinidine, cisapride, ranolazine, and verapamil) and demonstrated close agreement with their known clinical effects. Action potential triangulation was found to be a more sensitive metric for predicting proarrhythmic risk associated with the primary mechanism of concern for pharmaceutical-induced fatal ventricular arrhythmias, delayed cardiac repolarization due to inhibition of the rapid delayed rectifier potassium channel, or hERG channel. This study advances human induced pluripotent stem cell-based three-dimensional cardiac tissue models as new approach methodologies that enable in vitro proarrhythmic risk assessment with high precision of quantitative metrics for understanding clinically relevant cardiotoxicity.

Surgical Management of Ebstein Anomaly: The Australia and New Zealand Experience.

BACKGROUND: Ebstein anomaly is a rare congenital anomaly of the tricuspid valve which presents challenges to cardiac surgeons due to the spectrum of the disease and the technical difficulty of valve repair. The natural history of the anomaly differs between patients presenting in the neonatal period to those presenting in adulthood. METHODS: A retrospective review of all patients >15 years of age with Ebstein anomaly, undergoing surgery on the tricuspid valve at 6 centers across Australia and New Zealand was performed. Patients from 1985 to 2019 were included in the study. RESULTS: A total of 125 patients were included in the study, 76 patients (60%) undergoing tricuspid valve repair, of which 23 patients underwent a Cone repair and 49 (40%) had a tricuspid valve replacement. The mean follow-up was 7.9 ± 7.3 years. Postoperatively, early mortality was 3 patients (2%) and 10-year survival was 91.5%. A postoperative pacemaker was required in 24 patients (19%). Reoperation was required in 21 patients (17%). There was no statistically significant difference in survival or reoperation between patients who underwent repair or replacement of the tricuspid valve; however, with a small number of patients in long-term follow-up. CONCLUSION: Older children and adult patients undergoing surgery for Ebstein anomaly in Australia and New Zealand experience good medium-term postoperative survival. Repair of the valve is achieved in a significant proportion of patients with increasing use and success with the Cone repair technique.

Linking in vivo muscle dynamics to in situ force-length and force-velocity reveals that guinea fowl lateral gastrocnemius operates at shorter than optimal lengths.

Force-length (F-L) and force-velocity (F-V) properties characterize skeletal muscle's intrinsic properties under controlled conditions, and it is thought that these properties can inform and predict in vivo muscle function. Here, we map dynamic in vivo operating range and mechanical function during walking and running, to the measured in situ F-L and F-V characteristics of guinea fowl (Numida meleagris) lateral gastrocnemius (LG), a primary ankle extensor. We use in vivo patterns of muscle tendon force, fascicle length, and activation to test the hypothesis that muscle fascicles operate at optimal lengths and velocities to maximize force or power production during walking and running. Our findings only partly support our hypothesis: in vivo LG velocities are consistent with optimizing power during work production, and economy of force at higher loads. However, LG does not operate at lengths on the force plateau (±5% Fmax) during force production. LG length was near L0 at the time of EMG onset but shortened rapidly such that force development during stance occurred almost entirely on the ascending limb of the F-L curve, at shorter than optimal lengths. These data suggest that muscle fascicles shorten across optimal lengths in late swing, to optimize the potential for rapid force development near the swing-stance transition. This may provide resistance against unexpected perturbations that require rapid force development at foot contact. We also found evidence of passive force rise (in absence of EMG activity) in late swing, at lengths where passive force is zero in situ, suggesting that dynamic history dependent and viscoelastic effects may contribute to in vivo force development. Direct comparison of in vivo work loops and physiological operating ranges to traditional measures of F-L and F-V properties suggests the need for new approaches to characterize dynamic muscle properties in controlled conditions that more closely resemble in vivo dynamics.

Safety of zoster vaccine in adults from a large managed-care cohort: a Vaccine Safety Datalink study.

OBJECTIVES: The aim of this study was to examine a large cohort of adults who received the zoster vaccine for evidence of an increased risk of prespecified adverse events requiring medical attention. DESIGN: Two self-comparison approaches, including a case-centred approach and a self-controlled case series (SCCS) analysis were used. SETTING: Eight managed-care organizations participating in the Vaccine Safety Datalink project in the United States. SUBJECTS: A total of 193 083 adults aged 50 and older receiving a zoster vaccine from 1 January 2007 to 31 December 2008 were included. MAIN OUTCOME MEASURES: Prespecified adverse events were identified by aggregated International Classification of Diseases, Ninth Revision (ICD-9) codes in automated health plan datasets. RESULTS: The risk of allergic reaction was significantly increased within 1-7 days of vaccination [relative risk = 2.13, 95% confidence interval (CI): 1.87-2.40 by case-centred method and relative rate = 2.32, 95% CI: 1.85-2.91 by SCCS]. No increased risk was found for the following adverse event groupings: cerebrovascular events; cardiovascular events; meningitis; encephalitis; and encephalopathy; and Ramsay-Hunt syndrome and Bell's palsy. CONCLUSIONS: The results of this study support the findings from the prelicensure clinical trials, providing reassurance that the zoster vaccine is generally safe and well-tolerated with a small increased risk of allergic reactions in 1-7 days after vaccination.

Kinematic trajectories in response to speed perturbations in walking suggest modular task-level control of leg angle and length.

Navigating complex terrains requires dynamic interactions between the substrate, musculoskeletal and sensorimotor systems. Current perturbation studies have mostly used visible terrain height perturbations, which do not allow us to distinguish among the neuromechanical contributions of feedforward control, feedback-mediated and mechanical perturbation responses. Here, we use treadmill belt speed perturbations to induce a targeted perturbation to foot speed only, and without terrain-induced changes in joint posture and leg loading at stance onset. Based on previous studies suggesting a proximo-distal gradient in neuromechanical control, we hypothesized that distal joints would exhibit larger changes in joint kinematics, compared to proximal joints. Additionally, we expected birds to use feedforward strategies to increase the intrinsic stability of gait. To test these hypotheses, seven adult guinea fowl were video recorded while walking on a motorized treadmill, during both steady and perturbed trials. Perturbations consisted of repeated exposures to a deceleration and acceleration of the treadmill belt speed. Surprisingly, we found that joint angular trajectories and center of mass fluctuations remain very similar, despite substantial perturbation of foot velocity by the treadmill belt. Hip joint angular trajectories exhibit the largest changes, with the birds adopting a slightly more flexed position across all perturbed strides. Additionally, we observed increased stride duration across all strides, consistent with feedforward changes in the control strategy. The speed perturbations mainly influenced the timing of stance and swing, with the largest kinematic changes in the strides directly following a deceleration. Our findings do not support the general hypothesis of a proximo-distal gradient in joint control, as distal joint kinematics remain largely unchanged. Instead, we find that leg angular trajectory and the timing of stance and swing are most sensitive to this specific perturbation, and leg length actuation remains largely unchanged. Our results are consistent with modular task-level control of leg length and leg angle actuation, with different neuromechanical control and perturbation sensitivity in each actuation mode. Distal joints appear to be sensitive to changes in vertical loading but not foot fore-aft velocity. Future directions should include in vivo studies of muscle activation and force-length dynamics to provide more direct evidence of the sensorimotor control strategies for stability in response to belt speed perturbations.

Segmentation of epithelium in H&E stained odontogenic cysts.

An algorithm for the automated segmentation of epithelial tissue in digital images of histologic tissue sections of odontogenic cysts (cysts originating from residual odontogenic epithelium) is presented. The algorithm features an image standardization process that greatly reduces variation in luminance and chrominance between images due to variations in sample preparation. Segmentation of the epithelial regions of images uses an algorithm based on binary graph cuts where graph weights depend on probabilities obtained from colour histogram models of epithelium and stroma image regions. Algorithm training used a data set of 38 images of four types of odontogenic cyst and was tested using a separate data set of 35 images of the same four cyst types. The best parameters for the segmentation algorithm were determined using a response-surface optimizer. The best parameter set resulted in an overall mean (± std. dev.) sensitivity of 91.5 ± 17% and overall mean specificity of 85.1 ± 18.6% on the training set. Particularly good results were obtained for dentigerous and odontogenic keratocysts for which the mean sensitivities/specificities were 91.9 ± 6.15%/97.4 ± 2.15% and 96.1 ± 1.98%/98.7 ± 3.16%, respectively. Our method is potentially applicable to many pathological conditions in similar tissues, such as skin and mucous membranes where there is a clear microscopic distinction between epithelium and connective tissues.

The novel Mechanical Ventilator Milano for the COVID-19 pandemic.

This paper presents the Mechanical Ventilator Milano (MVM), a novel intensive therapy mechanical ventilator designed for rapid, large-scale, low-cost production for the COVID-19 pandemic. Free of moving mechanical parts and requiring only a source of compressed oxygen and medical air to operate, the MVM is designed to support the long-term invasive ventilation often required for COVID-19 patients and operates in pressure-regulated ventilation modes, which minimize the risk of furthering lung trauma. The MVM was extensively tested against ISO standards in the laboratory using a breathing simulator, with good agreement between input and measured breathing parameters and performing correctly in response to fault conditions and stability tests. The MVM has obtained Emergency Use Authorization by U.S. Food and Drug Administration (FDA) for use in healthcare settings during the COVID-19 pandemic and Health Canada Medical Device Authorization for Importation or Sale, under Interim Order for Use in Relation to COVID-19. Following these certifications, mass production is ongoing and distribution is under way in several countries. The MVM was designed, tested, prepared for certification, and mass produced in the space of a few months by a unique collaboration of respiratory healthcare professionals and experimental physicists, working with industrial partners, and is an excellent ventilator candidate for this pandemic anywhere in the world.

Functional and biochemical characterization of a secreted I-J(+) suppressor factor that binds to immunoglobulin.

A secreted product of a T cell leukemic cell line, LH-8, was examined for its biochemical and biological properties. The factor that we have termed Immunoglobulin-Binding T cell Suppressor Factor (IgB-TsF) was shown to be suppressive for the in vitro and in vivo humoral response to a variety (but not all) antigens tested. The cell surface phenotype of the LH-8.1 subclone was M.Ig(-), Thy-1(+), L3T4(-), Lyt-2(+), FcR(-), MAC-1(-), and H-2b(+). In addition, both the cell surface and secreted factor, IgB-TsF, of LH-8.1 expressed determinants that were recognized by anti-I-Jb mAbs but not by an anti-I-Jd monoclonal. The same factor also retained an affinity for the Fc portion of approximately 30% of randomly selected, purified mAbs. This binding could be abolished if the Fab or F(ab')2 fragments of these mAb were used, but was found to be unrelated to isotype of the respective mAbs. Using subclones that expressed quantitative differences in their ability to exert suppression as sources of biosynthetically labeled IgB-TsF, we have shown the suppressor activity correlated with a single, 28 kD protein. Furthermore, comparisons of these same subclones that differ in their suppressor activity, do not show any direct correlation of this biological activity with the expression of the previously described T cell receptor genes. It also suggests that at least some suppressor cell subsets may use the same or related family of T cell receptor genes for their recognitive stage of activation as helper and cytotoxic T cell subsets, but not for their effector stage of immunologic suppression.

Insomnia and its relationship to health-care utilization, work absenteeism, productivity and accidents.

BACKGROUND AND PURPOSE: To document and provide a micro analysis of the relationship between insomnia and health problems, health-care use, absenteeism, productivity and accidents. PARTICIPANTS AND METHODS: A population-based sample of 953 French-speaking adults from Québec, Canada. Participants were categorized as having insomnia syndrome (SYND) or insomnia symptoms (SYMPT) or as good sleepers (GS). They completed questionnaires on sleep, health, use of health-care services and products, accidents, work absences and reduced work productivity. Data were also obtained from the Québec-government-administered health insurance board on selected variables (e.g., consultations with health-care professionals, diagnoses). RESULTS: There were significantly more individuals in the SYND group relative to the GS group reporting at least one chronic health problem (83% vs. 53%; OR: 2.78) and who had consulted a health-care professional in the past year (81% vs. 60%; OR: 2.8). There were also higher proportions of individuals in the SYND group than in the GS group who had used prescription medications (57% vs. 30.7%; OR: 2.8), most notably to treat insomnia, mood and anxiety disorders, or who had used over-the-counter products (75.6% vs. 62.0%; OR: 1.8) and alcohol as a sleep aid (17.8% vs. 3.9%; OR: 4.6). In terms of daytime function, 25.0% of the SYND had been absent from work relative to 17.1% of GS (OR: 1.7), 40.6% reported having experienced reduced productivity compared to 12.3% of GS (OR: 4.8) and non-motor-vehicle accidents occurred at higher rates in the SYND group (12.5% vs. 6.4% for GS; OR: 2.4). No differences were found for hospitalisations or motor-vehicle accidents. Most of the associations remained significant even after controlling for psychiatric comorbidity. Rates for the SYMPT group were situated between SYND and GS on all major dependent variables. Furthermore, insomnia and fatigue were perceived as contributing significantly to accidents, absences and decreased work productivity, regardless of insomnia status. CONCLUSIONS: This study indicates that insomnia is associated with significant morbidity in terms of health problems and health-care utilization, work absenteeism and reduced productivity, and risk of non-motor-vehicle accidents. Future studies should evaluate whether treating insomnia can reverse this morbidity.

Gene expression analysis by transcript profiling coupled to a gene database query.

We describe an mRNA profiling technique for determining differential gene expression that utilizes, but does not require, prior knowledge of gene sequences. This method permits high-throughput reproducible detection of most expressed sequences with a sensitivity of greater than 1 part in 100,000. Gene identification by database query of a restriction endonuclease fingerprint, confirmed by competitive PCR using gene-specific oligonucleotides, facilitates gene discovery by minimizing isolation procedures. This process, called GeneCalling, was validated by analysis of the gene expression profiles of normal and hypertrophic rat hearts following in vivo pressure overload.

Adenosine diphosphate platelet dysfunction on thromboelastogram is independently associated with increased morality in traumatic brain injury.

PURPOSE: The purpose of this study is to determine if adenosine diphosphate (ADP) platelet dysfunction on thromboelastogram (TEG) is associated with increased in-hospital mortality in patients with head trauma. The hypothesis is that ADP dysfunction is associated with increased mortality. METHODS: This retrospective review evaluated trauma patients admitted to a level 1 trauma center from February 2011 to October 2013 who received a TEG. Patients were included if the TEG was drawn within the first 24 h of admission and the head abbreviated injury score was greater than or equal to three. Patients were categorized as severe ADP dysfunction if the degree of ADP inhibition on TEG exceeded 60 %. RESULTS: A total of 90 patients were included (no ADP dysfunction n = 37; ADP dysfunction n = 53). Initial Glasgow Coma Scale [GCS (12 ± 4 vs. 11 ± 5; p = 0.26)] and use of pre-injury antiplatelet agents (30 vs. 28 %; p = 0.88) were similar. Patients with ADP dysfunction on TEG had a higher in-hospital mortality rate (8 vs. 32 %; p < 0.01). ADP dysfunction was independently associated with in-hospital mortality upon fixed logistic regression (OR 6.2; 95 % CI 1.2-33) while controlling for age, gender, hypotension, pre-injury antiplatelet agents, GCS and Injury Severity Score. CONCLUSION: ADP dysfunction on TEG is associated with increased mortality in patients with traumatic brain injury.

Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors.

BACKGROUND AND PURPOSE: To estimate the prevalence of insomnia symptoms and syndrome in the general population, describe the types of self-help treatments and consultations initiated for insomnia, and examine help-seeking determinants. PATIENTS AND METHODS: A randomly selected sample of 2001 French-speaking adults from the province of Quebec (Canada) responded to a telephone survey about sleep, insomnia, and its treatments. RESULTS: Of the total sample, 25.3% were dissatisfied with their sleep, 29.9% reported insomnia symptoms, and 9.5% met criteria for an insomnia syndrome. Thirteen percent of the respondents had consulted a healthcare provider specifically for insomnia in their lifetime, with general practitioners being the most frequently consulted. Daytime fatigue (48%), psychological distress (40%), and physical discomfort (22%) were the main determinants prompting individuals with insomnia to seek treatment. Of the total sample, 15% had used at least once herbal/dietary products to facilitate sleep and 11% had used prescribed sleep medications in the year preceding the survey. Other self-help strategies employed to facilitate sleep included reading, listening to music, and relaxation. CONCLUSIONS: These findings confirm the high prevalence of insomnia in the general population. While few insomnia sufferers seek professional consultations, many individuals initiate self-help treatments, particularly when daytime impairments such as fatigue become more noticeable. Improved knowledge of the determinants of help-seeking behaviors could guide the development of effective public health prevention and intervention programs to promote healthy sleep.

Intracranial pressure monitoring: modeling cerebrovascular pressure transmission.

OBJECTIVES: To examine changes in cerebrovascular pressure transmission derived from arterial blood pressure (ABP) and intracranial pressure (ICP) recordings by autoregressive moving average modeling technique. METHODS: Digitized ICP and ABP recordings were obtained from patients with brain injury. Two groups were defined: Group A with 4 patients who demonstrated plateau waves, and Group B with 4 intracranial hypertensive, hypoperfused patients. For each 16.5 s interval, mean values of ICP, ABP, cerebral perfusion pressure (CPP), and corresponding highest modal frequency (HMF) of cerebrovascular pressure transmission were computed. RESULTS: Mean values of CPP and HMF of 56.2 mmHg and 2.0 Hz for Group A were significantly higher (p < 0.005) than corresponding mean values of 31.9 mmHg and 0.744 Hz for Group B. The mean value of the slope of the regression line between HMF and CPP for group A of -0.034 Hz/mmHg was significantly different (p < 0.025) than the mean value of 0.0077 Hz/mmHg for Group B. Computations of HMF, pressure reactivity, and correlation pressure reactivity index on continuous pressure recordings are illustrated. CONCLUSIONS: Values of HMF of cerebrovascular pressure transmission are inversely related to CPP when pressure regulation is thought to be intact, and directly related when regulation is likely lost.

Intratumor maturational heterogeneity within the murine myeloma MOPC-315.

The murine myeloma MOPC-315 secretes a paraprotein which binds dinitrophenylated compounds. Maturational subsets which mimic normal B-cell differentiation were shown to exist within this monoclonal neoplasm. The maturational subsets were defined by an in vivo stem cell activity (plasmacytoma colony-forming unit-spleen), DNA synthesis ([3H]thymidine incorporation), membrane-bound paraprotein, and cells secreting the MOPC-315 paraprotein. Velocity sedimentation at unit gravity separated cells enriched for secreting the MOPC0-315 protein (14.6 mm/hr) from the plasmacytoma colony-forming unit-spleen enriched population (9.3 mm/hr). An in vivo sequential analysis of the appearance of tumor (i.v. challenge) in the spleen of BALB/c hosts did not reveal any discordant appearance of these same maturational subsets with respect to time. The MOPC-315 myeloma contains maturational subsets that mimic normal B-cell differentiation and apparently differentiates during a very early stage of its evolution within the host.

Seed-specific overexpression of phytoene synthase: increase in carotenoids and other metabolic effects

A bacterial phytoene synthase (crtB) gene was overexpressed in a seed-specific manner and the protein product targeted to the plastid in Brassica napus (canola). The resultant embryos from these transgenic plants were visibly orange and the mature seed contained up to a 50-fold increase in carotenoids. The predominant carotenoids accumulating in the seeds of the transgenic plants were alpha and beta-carotene. Other precursors such as phytoene were also detected. Lutein, the predominant carotenoid in control seeds, was not substantially increased in the transgenics. The total amount of carotenoids in these seeds is now equivalent to or greater than those seen in the mesocarp of oil palm. Other metabolites in the isoprenoid pathway were examined in these seeds. Sterol levels remained essentially the same, while tocopherol levels decreased significantly as compared to non-transgenic controls. Chlorophyll levels were also reduced in developing transgenic seed. Additionally, the fatty acyl composition was altered with the transgenic seeds having a relatively higher percentage of the 18 : 1 (oleic acid) component and a decreased percentage of the 18 : 2 (linoleic acid) and 18 : 3 (linolenic acid) components. This dramatic increase in flux through the carotenoid pathway and the other metabolic effects are discussed.

Plateau waves: changes of cerebrovascular pressure transmission.

OBJECTIVE: To test the validity of the hypothesis that active vasodilatation and vasoconstriction underlie the occurrence of intracranial pressure (ICP) plateau waves by evaluating corresponding changes of cerebrovascular pressure transmission of arterial blood pressure (ABP) to ICP. METHODS: Digitized recordings of ICP and ABP sampled at 30 Hz were obtained from nine patients with traumatic brain injury. For each 16.5 s recording interval mean values of ICP, ABP, cerebral perfusion pressure (CPP), and the corresponding highest modal frequency (HMF) of cerebrovascular pressure transmission were calculated. RESULTS: Mean ICP and HMF significantly increased (P < 0.003) and mean CPP decreased significantly (P < 0.00036) at onset of the wave. Conversely at termination, mean ICP and HMF significantly decreased (P < 0.026) and mean CPP significantly increased (P < 0.028). In addition, the strong negative correlations between mean ICP and mean CPP (r = -0.87) and mean HMF and CPP (r = -0.87) were demonstrated. CONCLUSION: The findings that HMF increased at onset and decreased at the termination of plateau wave support the validity of the vasodilatatory/constriction cascade model that postulates active vasodilation at the onset and active vasoconstriction of the cerebrovascular bed at the termination of a plateau wave.

Molecular analysis of human immunoglobulin V lambda germline genes: subgroups V lambda III and V lambda IV.

Three human immunoglobulin V lambda germline genes have been isolated: two from the V lambda IV subgroup and one from the V lambda III subgroup. The V lambda III gene and one of the V lambda IV genes appear to be functional (each being utilized in at least two expressed V lambda genes), despite deviations from the reported consensus sequences in their promoter TATA-box and recombination signal sequence elements. The other V lambda IV gene is a pseudogene. Of the 20 human V lambda germline genes characterized to date, 45% are pseudogenes or vestigial genes.

Molecular characterization of the human immunoglobulin V lambda I germline gene repertoire.

To advance our understanding of the human immunoglobulin V lambda germline gene contribution to normal as well as autoimmune responses, we have isolated and sequenced six germline genes of the V lambda I subgroup. These genes can be divided into three sub-subgroups on the basis of greater than or equal to 93% nucleotide sequence homology and greater than or equal to 88% deduced amino acid sequence similarity. Examination of all cDNA and protein sequences available for expressed V lambda I genes supports the assignment of these three sub-subgroups. Sequence comparisons also suggest that germline gene members of two of these sub-subgroups, I-a and I-b, are preferentially utilized in the expressed V lambda I repertoire. This finding may be at least partially attributable to regulatory sequence abnormalities apparent in two of the other V lambda I germline genes (Humlv101 and Humlv104) which may interfere with their expression.

Early loss of blue-sensitive color vision in patients with type I diabetes.

Existing methods for early detection of ocular injury from diabetes have serious limitations. We describe a new method, measuring visual flicker discrimination of the blue-sensitive mechanism of vision. This method is noninvasive, quantitative, and capable of distinguishing two types of impairment. Blue-flicker discrimination was measured in 10 adults with type I (insulin-dependent) diabetes for less than 5 yr. Although no evidence of diabetic changes was detected by careful ophthalmic examination by an experienced ophthalmologist, 12 of 19 eyes (63%) had flicker discrimination scores considered abnormal in comparison with those of a control group, and 8 of 10 subjects (80%) had at least 1 eye with abnormal performance. In all but 2 abnormal eyes the deficit of blue-flicker discrimination was of the "absorptive" type, suggesting increased absorbance or scattering of blue light in the optical media. These data show that a functional impairment of vision can be measured very early in the course of type I diabetes, before visible retinopathy is present, and suggest this test procedure may have both investigative and clinical applications.