Reciprocal Associations Between Language Ability and Social Functioning Development in Pre-verbal Autistic Children.

Longitudinal research on language abilities and social functioning in young children suggests that gains in one domain affect gains in the other. However, few studies have examined inter-relations of language and social functioning jointly among young children diagnosed with autism spectrum disorder (ASD). Pre-verbal toddlers with ASD are a group of particular clinical relevance, given that greater language abilities at school entry have been associated with positive long-term adjustment in many areas, including adaptive and social functioning. Reduced attention to and engagement in social interactions among autistic toddlers who are not yet speaking may interfere with language development concurrently and over time. The present study examined reciprocal associations between language ability and social functioning over a 2-year period across three time points in a sample of 90 pre-verbal autistic toddlers using cross-lagged panel analyses conducted in MPlus. Cross-lagged panel analyses revealed significant within-timepoint synchronous correlations, within-domain autoregressive paths over time, and as hypothesized, reciprocal significance in all cross-lagged paths. For very young pre-verbal children with ASD, language ability and social functioning appear to exert concurrent and cascading developmental influences on one another. Targeting both language and social functioning simultaneously may enhance intervention efficacy for very young pre-verbal children with ASD.

Options for imaging cellular therapeutics in vivo: a multi-stakeholder perspective.

Cell-based therapies have been making great advances toward clinical reality. Despite the increase in trial activity, few therapies have successfully navigated late-phase clinical trials and received market authorization. One possible explanation for this is that additional tools and technologies to enable their development have only recently become available. To support the safety evaluation of cell therapies, the Health and Environmental Sciences Institute Cell Therapy-Tracking, Circulation and Safety Committee, a multisector collaborative committee, polled the attendees of the 2017 International Society for Cell & Gene Therapy conference in London, UK, to understand the gaps and needs that cell therapy developers have encountered regarding safety evaluations in vivo. The goal of the survey was to collect information to inform stakeholders of areas of interest that can help ensure the safe use of cellular therapeutics in the clinic. This review is a response to the cellular imaging interests of those respondents. The authors offer a brief overview of available technologies and then highlight the areas of interest from the survey by describing how imaging technologies can meet those needs. The areas of interest include imaging of cells over time, sensitivity of imaging modalities, ability to quantify cells, imaging cellular survival and differentiation and safety concerns around adding imaging agents to cellular therapy protocols. The Health and Environmental Sciences Institute Cell Therapy-Tracking, Circulation and Safety Committee believes that the ability to understand therapeutic cell fate is vital for determining and understanding cell therapy efficacy and safety and offers this review to aid in those needs. An aim of this article is to share the available imaging technologies with the cell therapy community to demonstrate how these technologies can accomplish unmet needs throughout the translational process and strengthen the understanding of cellular therapeutics.

Defining recovery trajectories after shoulder arthroplasty: a latent class analysis of patient-reported outcomes.

BACKGROUND: Patients undergoing total shoulder arthroplasty (TSA) can have varying levels of improvement after surgery. As patients typically demonstrate a nonlinear recovery trajectory, advanced analysis investigating the degrees of variation in outcomes is needed. Latent class analysis (LCA) is a mixed and multilevel model that estimates random slope variance to evaluate heterogeneity in outcome patterns among patient subgroups and can be used to outline differing recovery trajectories. The purpose of this study was to determine recovery trajectory patterns after TSA and to identify factors that predict a given trajectory. METHODS: Data from a prospectively collected single institutional database of patients undergoing anatomic and reverse TSA were utilized. Patients were included if they had American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores preoperatively, as well as postoperative scores at 6 weeks, 6 months, 1 year, and 2 years. Patients were excluded if they underwent a revision procedure or hemiarthroplasty or had prior infection. LCA was used to subdivide the patient cohort into subclasses based on postoperative recovery trajectory. This was performed for all patients as well as anatomic TSA and reverse TSA as separate groups. Unpaired Student t tests, analysis of variance, and Fisher exact test were used to compare classes based on factors including age, body mass index, sex, preoperative diagnosis, and type of arthroplasty. RESULTS: A total of 244 TSAs were included in the final analysis, comprising 89 anatomic TSA and 155 reverse TSA. In the combined group, LCA modeling revealed 3 patterns for recovery: Resistant Responders had low baseline scores (ASES < 30) and poor final results (ASES < 50), Steady Progressors had moderate baseline scores (ASES 30-50) with moderate final results (ASES 50-75), and High Performers had moderate baseline scores (ASES > 50) with excellent final results (ASES > 75). For anatomic TSA, we identified Delayed Responders with moderate baseline scores and a delayed response before ultimately achieving moderate final results, Steady Progressors with moderate baseline scores and a steady progression to achieve moderate final results, and High Performers who had moderate baseline scores and excellent final results. For reverse TSA, we identified Late Regressors with low baseline scores and poor final results, Steady Progressors with moderate baseline scores and moderate final results, and High Performers with moderate baseline scores and excellent final results. CONCLUSIONS: Patients recover in a heterogenous manner following TSA. Through LCA, we identified different recovery trajectories for patients undergoing anatomic TSA and reverse TSA.

Do patient outcomes and follow-up completion rates after shoulder arthroplasty differ based on insurance payor?

BACKGROUND: Disparities associated with socioeconomic status (SES) and insurance coverage have been shown to affect outcomes in different medical conditions and surgical procedures. We hypothesized that patients insured by Medicaid will be associated with lower follow-up rates and inferior outcomes relative to those with Medicare or private insurance. METHODS: Patients undergoing shoulder arthroplasty, including anatomic total shoulder arthroplasty, reverse arthroplasty, and hemiarthroplasty, were enrolled preoperatively in an institutional database. Preoperative demographics, payor (Medicaid, Medicare, or private insurance), and baseline American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) scores were recorded. Postoperatively, patients completed ASES scores at multiple time points. Follow-up completion rate was calculated as the number of follow-up visits completed relative to possible visits. Continuous variables were compared between groups with 1-way analyses of variance, and chi-squared tests were used for categorical variables. Significance was defined as P < .05. RESULTS: There were 491 shoulder replacements performed for 438 patients from 2012-2017. The mean follow-up completed percentage was significantly lower (P < .001) for Medicaid patients (62.6% ± 33.7%) relative to Medicare patients (80.2% ± 26.7%; P < .001) and private insurance patients (77.8% ± 22.1%; P = .001). The ASES Composite score increased significantly for all patients from baseline to final follow-up. At each time point, including before surgery and each postoperative time point, patients with Medicaid insurance had significantly lower ASES Composite scores. The final ASES Composite score was significantly lower in the Medicaid patients (66.1 ± 28.7) relative to private insurance patients (78.3 ± 20.8; P = .023). Medicaid patients had significantly lower preoperative (P < .001) and postoperative (P = .018) ASES Pain subscores. In multivariate regression analysis, Medicaid insurance was associated with both inferior preoperative and postoperative ASES scores relative to patients with Medicare or private insurance. CONCLUSIONS: We observed that all patients, regardless of insurance payor, improved by similar magnitudes after shoulder arthroplasty, though patients with Medicaid insurance had significantly lower preoperative and postoperative ASES scores, primarily because of the ASES Pain subscore. Patients with Medicaid insurance also have lower follow-up rates than other payors.

Treatment of Labral Calcification in the Setting of Femoroacetabular Impingement Syndrome With Arthroscopic Calcification Excision, Labral Repair, and Osteoplasty Improves Outcomes.

PURPOSE: To describe the diagnosis and 2-year outcomes of arthroscopic treatment for labral calcification in the setting of femoroacetabular impingement syndrome (FAIS). METHODS: A retrospective analysis was performed from a prospectively collected database of patients with FAIS undergoing hip arthroscopy. Patients with FAIS with labral calcification were differentiated radiographically from patients with other paralabral radiopaque densities such as os acetabuli, acetabular rim fractures, and labral ossification. Patients with FAIS with labral calcification were treated with arthroscopic calcification excision, labral repair, and osteoplasty and matched by age, sex, and body mass index with a cohort of patients with FAIS without labral calcifications who underwent labral repair and osteoplasty. Pre- and 2 years postoperatively, patients completed patient-reported outcome (PRO) scores including the modified Harris Hip Score, Hip disability and Osteoarthritis Outcome Score (HOOS), 12-item Short-Form survey, and visual analog scale. RESULTS: In total, 40 hips (21 male, 19 female) with FAIS and labral calcification were included (age 36.8 ± 8.1, body mass index, 25.9 ± 4.5). Patients with FAIS with labral calcification demonstrated similar significant PRO score improvements compared with a matched cohort of patients with FAIS without labral calcification at 2 years after surgery (visual analog scale: (-)2.3 ± 0.4, (-)2.7 ± 0.5, modified Harris Hip Score: 16.1 ± 2.6, 17.1 ± 3.2; HOOS symptoms: 21.9 ± 3.7, 18.6 ± 3.6; HOOS pain: 22.1 ± 3.0, 25.0 ± 3.5; HOOS activities of daily living: 20.2 ± 2.8, 23.8 ± 3.3; HOOS sport: 35.6 ± 5.0, 35.6 ± 4.1; HOOS quality of life: 36.9 ± 4.5, 37.5 ± 4.4; 12-item Short-Form survey physical component summary: 15.5 ± 2.3, 20.1 ± 2.1, respectively). Both cohorts achieved minimal clinically important differences at equivalent rates (60%-82.5%) for all PRO scores. CONCLUSIONS: Patients with labral calcification in the setting of FAIS can be effectively treated with arthroscopic calcification excision, labral repair, and osteoplasty. These patients demonstrate significant improvements in patient-reported outcomes and achievement of minimal clinically important differences at 2 years similar to patients undergoing arthroscopic treatment for FAIS without labral calcification. LEVEL OF EVIDENCE: Level III, matched cohort study.

Patellar tendon reconstruction with hamstring autograft for the treatment of chronic irreparable patellar tendon injuries.

BACKGROUND: Patellar tendon injuries not amenable to primary repair present a challenging problem for surgeons and patients alike. No standard surgical technique exists for these injuries and few studies report outcomes after surgical treatment. METHODS: A retrospective analysis was conducted for patients undergoing surgical treatment for irreparable patellar tendon tears. Patients were treated with an indirect tendon reconstruction technique using high-strength suture to set initial patellar height and hamstring autograft for biologic augmentation. Patients who underwent this procedure between 2012 and 2018 and met minimum two-year follow-up with completion of all outcome measurements including KOOS, PROMIS, VAS pain and satisfaction scores were included. RESULTS: Eleven patients met inclusion criteria. Ten of eleven patients (91%) had intact repairs and final patient outcomes were collected at a mean of 54.9 ± 23.1 months after surgery. Only one patient experienced extensor lag at final follow-up (p < 0.001). The preoperative Caton-Dechamps ratio was 1.77 ± 0.58, which decreased to 0.98 ± 0.25 after surgery (p < 0.001). The mean postoperative KOOS ADL score was 61.5. The mean postoperative PROMIS Global Mental and Physical Health scores were 46.9 ± 8.7 and 42.0 ± 9.8. Post-operative mean VAS satisfaction score was 5.6 ± 3.4. CONCLUSIONS: Patellar tendon reconstruction with autologous hamstring tendon graft and suture augmentation allows for acceptable outcomes in the setting of patellar tendon disruption with segmental defects when direct repair is not possible.

Mechanochemical synthesis of 0D and 3D cesium lead mixed halide perovskites.

A simplified mechanochemical synthesis approach for Cs-containing mixed halide perovskite materials of lower and higher dimensionality (0D and 3D, respectively) is presented with stoichiometric control from their halide salts, CsX and PbX2 (X = Cl, Br, I). Excellent optical bandgap tunability through halide substitution is supported by property measurements and changes to the materials' structure. Complementary NMR and XRD methods, along with support from DFT calculations, reveal highly crystalline 0D and 3D solid solutions with a complex arrangement of [PbX6-xXx']4- pseudooctahedra caused by halide distribution about the Pb centre.

Sickle cell disease in the older adult.

Sickle cell disease (SCD) is an inherited haemoglobin disorder, associated with recurrent painful episodes, ongoing haemolytic anaemia and progressive multi-organ damage. Until the early 1990s, survival beyond the fourth decade for a patient with SCD was considered unusual and prompted case reports. Nowadays, in countries with developed health care systems, more than 90 percent of newborns with SCD survive into adulthood. Nevertheless, their life expectancy is still shortened by more than two decades compared to the general population. With an increasing life expectancy, SCD has now evolved into a debilitating disorder with substantial morbidity resulting from ongoing sickle cell vasculopathy and multi-organ damage. Limited data on health care issues of older adults with SCD poses multiple challenges to patients, their families and health care providers. In this review, we will address and discuss acute and chronic complications of SCD with a special focus on the older adult.

Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 decades.

BACKGROUND: Acute myeloid leukemia (AML) is the common form of acute leukemia in adults, accounting for over 80% of all acute leukemias in individuals aged >18 years. Overall 5-year survival remains poor in older AML patients; it is <5% in patients aged >65 years. In this study, the authors examined whether survival has improved for subsets of geriatric AML patients over 3 successive decades. METHODS: Surveillance, Epidemiology and End Results (SEER) data were used to determine trends in relative survival by age among 19,000 patients with AML over 3 successive decades (1977-1986, 1987-1996, and 1997-2006). Relative survival rates (RRs) with 95% confidence intervals (CIs) were calculated as measures of survival. RESULTS: Overall, the RRs increased for each successive decade (1977-1986, 1987-1996, and 1997-2006) in patients ages 65 to 74 years, with improvements in 12-month survival from 20%, to 25%, to 30%, respectively. Findings were similar for 24-month, 36-month, 48-month, and 60-month survival. However, survival rates did not improve in patients aged ≥75 years. The oldest old patients (aged ≥85 years) had the lowest survival rates, with no apparent improvement. CONCLUSIONS: This analysis of a large data set demonstrated that, although overall survival remained unsatisfactory among older patients, it improved in the younger old (ages 65-74 years). Survival of older old AML patients has not been favorably impacted by available AML therapies or supportive care, and intervention in this age group is best undertaken on a clinical trial.

Self-assembling nanocomplexes by combining ferumoxytol, heparin and protamine for cell tracking by magnetic resonance imaging.

We report on a new straightforward magnetic cell-labeling approach that combines three US Food and Drug Administration (FDA)-approved drugs--ferumoxytol, heparin and protamine--in serum-free medium to form self-assembling nanocomplexes that effectively label cells for in vivo magnetic resonance imaging (MRI). We observed that the ferumoxytol-heparin-protamine (HPF) nanocomplexes were stable in serum-free cell culture medium. HPF nanocomplexes show a threefold increase in T2 relaxivity compared to ferumoxytol. Electron microscopy showed internalized HPF in endosomes, which we confirmed by Prussian blue staining of labeled cells. There was no long-term effect or toxicity on cellular physiology or function of HPF-labeled hematopoietic stem cells, bone marrow stromal cells, neural stem cells or T cells when compared to controls. In vivo MRI detected 1,000 HPF-labeled cells implanted in rat brains. This HPF labeling method should facilitate the monitoring by MRI of infused or implanted cells in clinical trials.

Iron labeling and pre-clinical MRI visualization of therapeutic human neural stem cells in a murine glioma model.

BACKGROUND: Treatment strategies for the highly invasive brain tumor, glioblastoma multiforme, require that cells which have invaded into the surrounding brain be specifically targeted. The inherent tumor-tropism of neural stem cells (NSCs) to primary and invasive tumor foci can be exploited to deliver therapeutics to invasive brain tumor cells in humans. Use of the strategy of converting prodrug to drug via therapeutic transgenes delivered by immortalized therapeutic NSC lines have shown efficacy in animal models. Thus therapeutic NSCs are being proposed for use in human brain tumor clinical trials. In the context of NSC-based therapies, MRI can be used both to non-invasively follow dynamic spatio-temporal patterns of the NSC tumor targeting allowing for the optimization of treatment strategies and to assess efficacy of the therapy. Iron-labeling of cells allows their presence to be visualized and tracked by MRI. Thus we aimed to iron-label therapeutic NSCs without affecting their cellular physiology using a method likely to gain United States Federal Drug Administration (FDA) approval. METHODOLOGY: For human use, the characteristics of therapeutic Neural Stem Cells must be clearly defined with any pertubation to the cell including iron labeling requiring reanalysis of cellular physiology. Here, we studied the effect of iron-loading of the therapeutic NSCs, with ferumoxide-protamine sulfate complex (FE-Pro) on viability, proliferation, migratory properties and transgene expression, when compared to non-labeled cells. FE-Pro labeled NSCs were imaged by MRI at tumor sites, after intracranial administration into the hemisphere contralateral to the tumor, in an orthotopic human glioma xenograft mouse model. CONCLUSION: FE-Pro labeled NSCs retain their proliferative status, tumor tropism, and maintain stem cell character, while allowing in vivo cellular MRI tracking at 7 Tesla, to monitor their real-time migration and distribution at brain tumor sites. Of significance, this work directly supports the use of FE-Pro-labeled NSCs for real-time tracking in the clinical trial under development: "A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically modified Neural Stem Cells Expressing Escherichia coli Cytosine Deaminase for Treatment of Recurrent High-Grade Gliomas".

Can lean body mass be used to reduce the dose of heparin and protamine for obese patients undergoing cardiopulmonary bypass?

Increasing numbers of obese patients are presenting for cardiac surgery. The convention for heparin dose dictates that a bolus of 300 IU heparin per kilogram of total body weight (TBW) is administered before CPB. During CPB, the activated clotting time (ACT) is maintained for longer than 480 seconds. At the end of the procedure, protamine is administered to neutralize heparin and achieve hemostasis. Both of these drugs can have serious side effects: heparin can induce thrombocytopenia, and protamine has been known to cause reactions in patients allergic to fish, vasectomized men, and some patients with insulin-dependent diabetes. The calculation of lean body mass (LBM) may be a more accurate method of determining drug doses as opposed to TBW and may avoid giving obese patients a relative overdose of heparin, which must subsequently be neutralized with protamine. LBM can be determined by different methods. This study used bio-electrical impedance analysis as a simple, quick, and accurate method of calculating LBM. A comparison was made between two groups of patients whose body mass index (BMI) was >27 kg/m2: Group 1, n = 13, mean BMI = 32, mean body fat = 36% received the conventional dose of 300 IU/kg heparin for their TBW. Group 2, n = 14, mean BMI = 31, mean body fat = 35% received a dose of 300 IU/kg heparin for their calculated LBM. ACT was conducted before and after heparin administration. Additional heparin was administered as required to achieve target ACT > 400 s. Mean ACT results and total heparin doses were analyzed using unpaired two tailed t tests. Our results indicate that with care, a reduction of as much as 25% in the doses of heparin (p = 0.0001) and protamine can be achieved for a substantial number of patients classified as overweight or obese.

Field trial of efficacy of local compression immobilization first-aid technique in Russell's viper (Daboia russelii siamensis) bite patients.

A field trial of efficacy of local compression immobilization first-aid technique in 42 Russell's viper bite cases was studied and only 19 were envenomed. Proper immobilization was carried out in 3/13 immobilized cases. The average time of application of the pad was 1.12 hours (range 5 minutes to 7 hours) and the total duration of the pad application was 3 hours 40 minutes (range 30 minutes to 9 hours). Venom levels measured at the hospital before and at 15 and 30 minutes after release of the pad (n=10) showed a rise of 5 to 30 ng/ml of venom following release. Movement of venom antigen was found to be retarded in all cases (n=9) whose venom levels were measured at 15 and 30 minutes with the pad in place. Sixteen out of 19 cases had systemic envenoming, indicating that pad or immobilization alone is not effective in delaying spread of venom. The incidence of local necrosis 3/42 (8%) following use of the pad was comparable to that of the systemic cases without the pad. No ill effects were observed following its application for as long as 9 hours. Local blackening seen in 4/36 (10%) cases was likely to be result of a local venom effect.

Development of a high performance liquid chromatographic assay measuring mezlocillin in serum or tissue.

OBJECTIVE: This study evaluated the blood and uterine tissue concentration of mezlocillin, a broadspectrum penicillin. METHODS: We adapted a liquid chromatographic method to measure mezlocillin in serum and tissue. Mezlocillin reference standard was diluted in water, chromatographed on a reversed phase C18 column eluted at 1.5 ml/min with acetonitrile and phosphate buffer (1:3 v:v), and detected spectrophotometrically at 210 nm. Mezlocillin was administered to 14 premenopausal women scheduled to undergo vaginal hysterectomy. Each patient received a 4 g IV infusion of the drug 30 to 60 min prior to surgery. During surgery, tissue was removed from the uterine cervix and blood was obtained for assay of mezlocillin content. RESULTS: Chromatography of the mezlocillin standard furnished a discrete peak with a retention time of 2.4 min. The sensitivity of the assay was 0.1 microg/ml with a linear response up to 100 microg/ml. The correlation coefficient for the standard curve was 0.9997. When reference standard was diluted in pooled human serum, the assay was complicated by interfering compounds. These were removed by ether extraction. The sensitivity of the assay performed in serum was 3 microg/ml. Serum samples contained from 81.2 to 358 microg of mezlocillin/ml with an average serum concentration of 207.5 microg/ml. When serum containing a known amount of mezlocillin was homogenized for a period of time similar to that required to homogenize tissue samples, a deteatable loss of drug was observed and was applied as a correction factor to the measured tisulevels. After correction, the average tissue level was 117.2 microg/ml and ranged from 27% to 98% of the serum levels. CONCLUSIONS: The serum concentration of mezlocillin after IV infusion of 4 g was greater than that required to inhibit the majority of the most significant organisms responsible for post-hysterectomy sepsis. Although tissue levels appeared to be consistently lower than serum levels, they could be expected to provide an inhibitory effect against many of the bacterial strains that contaminate the surgical site.

Evaluation of vaginal malodor and efficacy of treatment by high performance ion exchange chromatography.

High performance ion exchange chromatography was employed to evaluate the presence of short chain organic acids in the vaginal fluid of a woman troubled by persistent foul vaginal odor, but who did not have typical bacterial vaginosis. The vaginal secretions from this patient were collected on a weighed cotton swab and eluted into water and extracted by acidified ether. Salts of the acids were back-extracted into aqueous solution and chromatographed on an H-form resin column and compared to commercially available standards. A strikingly large amount of caproic acid was found. The caproic acid disappeared after metronidazole therapy, and a subsequent follow-up chromatogram showed a predominance of lactic acid. The success of this technique in evaluating the present case suggests that such a method may prove useful in other types of vaginal infection.

Oxygen-regulated stimulons of Salmonella typhimurium identified by Mu d(Ap lac) operon fusions.

Using the technique of Mu d1(Ap lac)-directed lacZ operon fusions, several oxygen-regulated genetic loci were identified in Salmonella typhimurium. Thirteen anaerobically inducible and six aerobically inducible operon fusions were identified. Based on control by the oxrA and oxrB regulatory loci, the anti-lacZ fusions were grouped into three classes: class I loci were regulated by both oxr loci, class II genes were regulated by oxrA only, and class III loci were not affected by either regulatory locus. Several of the anti-lacZ fusions required growth in complex medium before they exhibited the inducible phenotype. While the expression of some of these loci was repressed when organisms were grown in nitrate, others were stimulated by nitrate. Fusions into the hyd and phs loci were identified among the isolated anti-lacZ fusions. Six oxygen-inducible (oxi) operon fusions were also identified. Two of the oxi loci mapped near oxygen-regulatory loci: oxiC near oxrA and oxiE near oxyR. However, neither fusion appeared to occur within the regulatory locus. The data presented serve to further define the aerobic and anaerobic stimulons of S. typhimurium but indicate additional regulatory circuits above those already defined.

NAD metabolism in Salmonella typhimurium: isolation of pyridine analogue supersensitive (pas) and pas suppressor mutants.

Mutants of Salmonella typhimurium supersensitive to the nicotinic acid analogue 6-amino-nicotinic acid (6ANA) were isolated as unable to grow on what are normally subinhibitory concentrations of the analogue. The mutations were classified on the basis of their map positions as pasA (89-92 units), pasB (66-69 units), pasC (18-22 units), pasD (18 units) and pasE (55 units). The mutants exhibited a wide range of minimal inhibitory concentrations towards 6ANA, and several were affected in terms of growth. The data suggest that most of the mutations probably reside in genes whose products utilize nicotinamide adenine dinucleotide (NAD) as a cofactor, the altered gene products being more sensitive to internal 6-amino NAD concentrations. Secondary mutations which suppress the Pas- phenotype were found to reside in the following NAD-related loci; pncB, nadB and nadD. Two of the pncB mutants appear to be affected in the expression of NAPRTase while several of the nadB mutants are apparently insensitive to feedback inhibition by internal NAD concentrations.