Estimating meaningful change thresholds for Skin Pain-Numeric Rating Scale, Sleep-Numeric Rating Scale and Dermatology Life Quality Index in patients with prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is characterized by intensely itchy nodules/lesions and skin pain, which can have a substantial impact on health-related quality of life (HRQoL). Treatment benefits on such symptoms and impacts are best assessed in trials using patient-reported outcome (PROs) instruments such as Skin Pain Numerical Rating Scale (NRS), Sleep-NRS and Dermatology Life Quality Index (DLQI). However, no guidance exists for interpreting meaningful changes in scores using these PROs in patients with PN. OBJECTIVES: The main objective was to derive within-patient (responder definition) and between-group improvement thresholds for interpreting Skin Pain-NRS, Sleep-NRS and DLQI total scores in patients with PN. The measurement properties of the three PROs were also evaluated. METHODS: Intention-to-treat (ITT), blinded and pooled data were used from the Phase 3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN. Anchor- and distribution-based methods were applied to derive responder definition and between-group thresholds for Skin Pain-NRS, Sleep-NRS and DLQI. Data were additionally used to examine the instrument measurement properties, including reliability, validity and responsiveness. RESULTS: A total of 311 patients (mean age 49.5 years, 65.3% female) were included in the pooled ITT population. The within-patient improvement threshold for Skin Pain-NRS was estimated as 4.0 points, 2.0 points for Sleep-NRS and 9.0 points for DLQI total score. A 1.5-point improvement in Skin Pain-NRS scores, 1.0-point in Sleep-NRS and 4.0-point in DLQI indicated a between-group meaningful change. Adequate to good psychometric properties were demonstrated for all three instruments. CONCLUSIONS: The results of this study can aid interpretation of Skin Pain-NRS, Sleep-NRS and DLQI scores in patients with PN in both clinical trials and clinical practice to better understand and treat PN-related skin pain and the impact of PN on sleep quality and HRQoL.

The efficacy and safety of dupilumab in Chinese patients with moderate-to-severe atopic dermatitis: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Dupilumab is an antibody against interleukin-4 receptor α, used in the treatment of atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of dupilumab in adult Chinese patients with moderate-to-severe AD. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group, phase III study, conducted between December 2018 and February 2020, patients with AD received dupilumab (300 mg) or placebo once every 2 weeks for 16 weeks, and were followed up for 12 weeks. The primary efficacy endpoint was the proportion of patients with both an Investigator's Global Assessment score of 0-1 and a reduction from baseline of ≥ 2 points at week 16. RESULTS: Overall, 165 patients (mean age 30·6 years; 71·5% male patients) were randomized; 82 patients were randomized to dupilumab and 83 patients were randomized to placebo. At week 16, 26·8% of patients in the dupilumab group and 4·8% of patients in the placebo group achieved the primary endpoint [difference 22·0%, 95% confidence interval (CI) 11·37-32·65; P < 0·001]. Compared with placebo, higher proportions of patients in the dupilumab group achieved ≥ 75% reduction in the Eczema Area and Severity Index score (57·3% vs. 14·5%; difference 42·9%, 95% CI 29·75-55·97; P < 0·001) and had ≥ 3-point (52·4% vs. 9·6%; difference 42·8%, 95% CI 30·26-55·34; P < 0·001) and ≥ 4-point (39·0% vs. 4·8%; difference 34·2%, 95% CI 22·69-45·72; P < 0·001) reductions in weekly average daily peak daily pruritus numerical rating scale scores. The incidence of treatment-emergent adverse events during the treatment period was similar in the two groups. The incidence of conjunctivitis, allergic conjunctivitis and injection site reaction was higher in the dupilumab group than in the placebo group. CONCLUSIONS: In adult Chinese patients, dupilumab was effective in improving the signs and symptoms of AD and demonstrated a favourable safety profile.

Dupilumab provides favourable long-term safety and efficacy in children aged ≥ 6 to < 12 years with uncontrolled severe atopic dermatitis: results from an open-label phase IIa study and subsequent phase III open-label extension study.

BACKGROUND: Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signalling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking. OBJECTIVES: To report the pharmacokinetic profile and long-term safety and efficacy of dupilumab in children (aged ≥ 6 to < 12 years) with severe AD. METHODS: Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open-label, ascending-dose, sequential cohort study and subsequent open-label extension (OLE) study. Patients received single-dose dupilumab 2 or 4 mg kg-1 followed by 8-week pharmacokinetic sampling, then 2 or 4 mg kg-1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentration-time profile and treatment-emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP-NRS) score. RESULTS: Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target-mediated pharmacokinetics characterized dupilumab concentrations (week 24-48 mean serum concentrations: 2 mg kg-1 , 61-77 mg L-1 ; 4 mg kg-1 , 143-181 mg L-1 ). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg-1 , 47%; 4 mg kg-1 , 56%) and AD exacerbation (29% and 13%, respectively). Single-dose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP-NRS improved by -37%/-33% and -17%/-20% at week 2 (phase IIa) and -92%/-84% and -70%/-58% at week 52 (OLE), respectively. CONCLUSIONS: These safety and efficacy results support the use of dupilumab as a continuous long-term treatment for children aged ≥ 6 to < 12 years with severe AD.

Characterizing a "Big Data" Cohort of Over 200,000 Low-Income U.S. Infants and Children for Obesity Research: The ADVANCE Early Life Cohort.

Introduction Low-income populations have elevated exposure to early life risk factors for obesity, but are understudied in longitudinal research. Our objective was to assess the utility of a cohort derived from electronic health record data from safety net clinics for investigation of obesity emerging in early life. Methods We examined data from the PCORNet ADVANCE Clinical Data Research Network, a national network of Federally-Qualified Health Centers serving >1.7 million safety net patients across the US. This cohort includes patients who, in 2012-2014, had ≥1 valid body mass index measure when they were 0-5 years of age. We characterized the cohort with respect to factors required for early life obesity research in vulnerable subgroups: sociodemographic diversity, weight status based on World Health Organization (<2 years) or Centers for Disease Control (≥2 years) growth curves, and data longitudinality. Results The cohort includes 216,473 children and is racially/ethnically diverse (e.g., 17.9% Black, 45.4% Hispanic). A majority (56.9%) had family incomes below the Federal Poverty Level (FPL); 32% were <50% of FPL. Among children <2 years, 7.6 and 5.3% had high and low weight-for-length, respectively. Among children 2-5 years, 15.0, 12.7 and 2.4% were overweight, obese, and severely obese, respectively; 5.3% were underweight. In the study period, 79.2% of children had ≥2 BMI measures. Among 4-5 year olds, 21.9% had >1 BMI measure when they were <2 years. Discussion The ADVANCE Early Life cohort offers unique opportunities to investigate early life determinants of obesity in the understudied population of low income and minority children.

Codominant Role of Interferon-γ- and Interleukin-17-Producing T Cells During Rejection in Full Facial Transplant Recipients.

Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-γ/interleukin-17-producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17-mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development.

Three-dimensional quantification of fibrosis and ossification after cochlear implantation via virtual re-sectioning: Potential implications for residual hearing.

Hearing preservation may be achieved initially in the majority of patients after cochlear implantation, however, a significant proportion of these patients experience delayed hearing loss months or years later. A prior histological report in a case of delayed hearing loss suggested a potential cochlear mechanical origin of this hearing loss due to tissue fibrosis, and older case series highlight the frequent findings of post-implantation fibrosis and neoosteogenesis though without a focus on the impact on residual hearing. Here we present the largest series (N = 20) of 3-dimensionally reconstructed cochleae based on digitally scanned histologic sections from patients who were implanted during their lifetime. All patients were implanted with multichannel electrodes via a cochleostomy or an extended round window insertion. A quantified analysis of intracochlear tissue formation was carried out via virtual re-sectioning orthogonal to the cochlear spiral. Intracochlear tissue formation was present in every case. On average 33% (SD 14%) of the total cochlear volume was occupied by new tissue formation, consisting of 26% (SD 12%) fibrous and 7% (SD 6%) bony tissue. The round window was completely covered by fibro-osseous tissue in 85% of cases and was associated with an obstruction of the cochlear aqueduct in 100%. The basal part of the basilar membrane was at least partially abutted by the electrode or new tissue formation in every case, while the apical region, corresponding with a characteristic frequency of < 500 Hz, appeared normal in 89%. This quantitative analysis shows that after cochlear implantation via extended round window or cochleostomy, intracochlear fibrosis and neoossification are present in all cases at anatomical locations that could impact normal inner ear mechanics.

A hypothalamic-thalamostriatal circuit that controls approach-avoidance conflict in rats.

Survival depends on a balance between seeking rewards and avoiding potential threats, but the neural circuits that regulate this motivational conflict remain largely unknown. Using an approach-food vs. avoid-predator threat conflict test in rats, we identified a subpopulation of neurons in the anterior portion of the paraventricular thalamic nucleus (aPVT) which express corticotrophin-releasing factor (CRF) and are preferentially recruited during conflict. Inactivation of aPVTCRF neurons during conflict biases animal's response toward food, whereas activation of these cells recapitulates the food-seeking suppression observed during conflict. aPVTCRF neurons project densely to the nucleus accumbens (NAc), and activity in this pathway reduces food seeking and increases avoidance. In addition, we identified the ventromedial hypothalamus (VMH) as a critical input to aPVTCRF neurons, and demonstrated that VMH-aPVT neurons mediate defensive behaviors exclusively during conflict. Together, our findings describe a hypothalamic-thalamostriatal circuit that suppresses reward-seeking behavior under the competing demands of avoiding threats.

Stabilization of acetylcholine receptors by exogenous ATP and its reversal by cAMP and calcium.

Innervation of the neuromuscular junction (nmj) affects the stability of acetylcholine receptors (AChRs). A neural factor that could affect AChR stabilization was studied using cultured muscle cells since they express two distinct populations of AChRs similar to those seen at the nmjs of denervated muscle. These two AChR populations are (in a ratio of 9 to 1) a rapidly degrading population (Rr) with a degradation half-life of approximately 1 d and a slowly degrading population (Rs) that can alternate between an accelerated form (half-life approximately 3-5 d) and a stabilized form (half-life approximately 10 d), depending upon the state of innervation of the muscle. Previous studies have shown that elevation of intracellular cAMP can stabilize the Rs, but not the Rr. We report here that in cultured rat muscle cells, exogenous ATP stabilized the degradation half-life of Rr and possibly also the Rs. Furthermore, pretreatment with ATP caused more stable AChRs to be inserted into the muscle membrane. Thus, in the presence of ATP, the degradation rates of the Rr and Rs overlap. This suggests that ATP released from the nerve may play an important role in the regulation of AChR degradation. Treatment with either the cAMP analogue dibutyryl-cAMP (dB-cAMP) or the calcium mobilizer ryanodine caused the ATP-stabilized Rr to accelerate back to a half-life of 1 d. Thus, at least three signaling systems (intracellular cAMP, Ca2+, and extracellular ATP) have the potential to interact with each other in the building of an adult neuromuscular junction.

Intrathecal interferon reduces exacerbations of multiple sclerosis.

Ten patients with multiple sclerosis who were treated with human fibroblast interferon (IFN-B) for 6 months showed a significant reduction in their exacerbation rates compared with their rates before treatment (P < .01). The IFN-B was administered intrathecally by serial lumbar punctures. There was no significant change in the exacerbation rates of ten multiple sclerosis control patients before and during the period of observation. The IFN-B recipients have now been on the study a mean of 1.5 years, the controls, 1.2 years. The clinical condition of five of the IFN-B recipients and one of the control patients has improved, whereas the condition of five of the controls and one of the IFN-B recipients has deteriorated (P < .036). These findings warrant cautious optimism about the efficacy of intrathecal IFN-B in altering the course of multiple sclerosis and support concepts of a viral or dysimmune etiology of the disease.

Appropriateness of colonoscopy in Europe (EPAGE II). Iron-deficiency anemia and hematochezia.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for the investigation of iron-deficiency anemia (IDA) and hematochezia, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews and primary studies regarding the evaluation and management of IDA and hematochezia was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: IDA occurs in 2 %-5 % of adult men and postmenopausal women. Examination of both the upper and lower gastrointestinal tract is recommended in patients with iron deficiency. Colonoscopy for IDA yields one colorectal cancer (CRC) in every 9-13 colonoscopies. Hematochezia is a well-recognized alarm symptom and such patients are likely to be referred for colonoscopy. Colonoscopy is unanimously recommended in patients aged > or = 50. Diverticulosis, vascular ectasias, and ischemic colitis are common causes of acute lower gastrointestinal bleeding (LGIB); CRC is found in 0.2 %-11 % of the colonoscopies performed for LGIB. Most patients with scant hematochezia have an anorectal or a distal source of bleeding. The expert panel considered most clinical indications for colonoscopy as appropriate in the presence of IDA (58 %) or hematochezia (83 %). CONCLUSION: Despite the limitations of the published studies, guidelines unanimously recommend colonoscopy for the investigation of IDA and hematochezia in patients aged > or = 50 years. These indications were also considered appropriate by EPAGE II, as were indications in patients at low risk for CRC with no obvious cause of bleeding found during adequate previous investigations.

Primary Neural Degeneration in the Human Cochlea: Evidence for Hidden Hearing Loss in the Aging Ear.

The noise-induced and age-related loss of synaptic connections between auditory-nerve fibers and cochlear hair cells is well-established from histopathology in several mammalian species; however, its prevalence in humans, as inferred from electrophysiological measures, remains controversial. Here we look for cochlear neuropathy in a temporal-bone study of "normal-aging" humans, using autopsy material from 20 subjects aged 0-89 yrs, with no history of otologic disease. Cochleas were immunostained to allow accurate quantification of surviving hair cells in the organ Corti and peripheral axons of auditory-nerve fibers. Mean loss of outer hair cells was 30-40% throughout the audiometric frequency range (0.25-8.0 kHz) in subjects over 60 yrs, with even greater losses at both apical (low-frequency) and basal (high-frequency) ends. In contrast, mean inner hair cell loss across audiometric frequencies was rarely >15%, at any age. Neural loss greatly exceeded inner hair cell loss, with 7/11 subjects over 60 yrs showing >60% loss of peripheral axons re the youngest subjects, and with the age-related slope of axonal loss outstripping the age-related loss of inner hair cells by almost 3:1. The results suggest that a large number of auditory neurons in the aging ear are disconnected from their hair cell targets. This primary neural degeneration would not affect the audiogram, but likely contributes to age-related hearing impairment, especially in noisy environments. Thus, therapies designed to regrow peripheral axons could provide clinically meaningful improvement in the aged ear.

Evaluating community health centers' adoption of a new global capitation payment (eCHANGE) study protocol.

Primary care patient-centered medical homes (PCMHs) are an effective healthcare delivery model. Evidence regarding the most effective payment models for increased coordination efforts is sparse. This protocol paper describes the evaluation of an Alternative Payment Methodology (APM) implemented in a subset of Oregon community health centers (CHCs), using a prospective matched observational design. The APM is a primary care payment reform intervention that changed Oregon's Medicaid payment for several CHCs from fee-for-service reimbursement to a per-member-per-month capitated payment. We will implement a difference-in-difference analytic approach to evaluate pre-post APM changes between intervention and control groups, including: 1) clinic-level outcomes, 2) patient-level clinical outcomes, and 3) patient-level econometric outcomes. Findings from the project will be of national significance, as there is a need for evidence regarding how novel payment methods might enhance PCMH capabilities and support their capacity to produce better quality and outcomes. If this capitated payment method is proven effective, study findings will inform dissemination of similar APMs nationwide.

Binding properties of high-density lipoprotein subfractions and low-density lipoproteins to rabbit hepatocytes.

Primary cultures of rabbit hepatocytes which were preincubated for 20 h in a medium containing lipoprotein-deficient serum subsequently bound, internalized and degraded 125I-labeled high-density lipoproteins2 (HDL2). The rate of degradation of HDL2 was constant in incubations from 3 to 25 h. As the concentration of HDL2 in the incubation medium was increased, binding reached saturation. At 37 degrees C, half-maximal binding (Km) was achieved at a concentration of 7.3 micrograms of HDL2 protein/ml (4.06 X 10(-8)M) and the maximum amount bound was 476 ng of HDL2 protein/mg of cell protein. At 4 degrees C, HDL2 had a Km of 18.6 micrograms protein/ml (1.03 X 10(-7)M). Unlabeled low-density lipoproteins (LDL) inhibited only at low concentrations of 125I-labeled HDL2. Quantification of 125I-labeled HDL2 binding to a specific receptor (based on incubation of cells at 4 degrees C with and without a 50-fold excess of unlabeled HDL) yielded a dissociation constant of 1.45 X 10(-7)M. Excess HDL2 inhibited the binding of both 125I-labeled HDL2 and 125I-labeled HDL3, but excess HDL3 did not affect the binding of 125I-labeled HDL3. Preincubation of hepatocytes in the presence of HDL resulted in only a 40% reduction in specific HDL2 receptors, whereas preincubation with LDL largely suppressed LDL receptors. HDL2 and LDL from control and hypercholesterolemic rabbits inhibited the degradation of 125I-labeled HDL2, but HDL3 did not. Treatment of HDL2 and LDL with cyclohexanedione eliminated their capacity to inhibit 125I-labeled HDL2 degradation, suggesting that apolipoprotein E plays a critical role in triggering the degradative process. The effect of incubation with HDL on subsequent 125I-labeled LDL binding was time-dependent: a 20 h preincubation with HDL reduced the amount of 125I-labeled LDL binding by 40%; there was a similar effect on LDL bound in 6 h but not on LDL bound in 3 h. The binding of 125I-labeled LDL to isolated liver cellular membranes demonstrated saturation kinetics at 4 degrees C and was inhibited by EDTA or excess LDL. The binding of 125I-labeled HDL2 was much lower than that of 125I-labeled LDL and was less inhibited by unlabeled lipoproteins. The binding of 125I-labeled HDL3 was not inhibited by any unlabeled lipoproteins. EDTA did not affect the binding of either HDL2 or HDL3 to isolated liver membranes. Hepatocytes incubated with [2-14C]acetate in the absence of lipoproteins incorporated more label into cellular cholesterol, nonsaponifiable lipids and total cellular lipid than hepatocytes incubated with [2-14C]acetate in the presence of any lipoprotein fraction. However, the level of 14C-labeled lipids released into the medium was higher in the presence of medium lipoproteins, indicating that the effect of those lipoproteins was on the rate of release of cellular lipids rather than on the rate of synthesis.

Metabolism of free and esterified cholesterol and apolipoproteins of plasma low and high density lipoproteins.

We studied the patterns of equilibration of free and esterified cholesterol between lipoprotein fractions of plasma separated by heparin-Mn2+ and of their disappearance from plasma and appearance in liver and bile. Free or esterified [4-14C]cholesterol in low density lipoproteins (LDL) and [7(n)-3H]cholesterol in high density lipoproteins (HDL2 or HDL3) were incubated together with plasma or injected simultaneously into squirrel monkeys. The isotope was alternated for successive experiments. Free cholesterol was equilibrated completely between lipoprotein classes within 30-45 min, but esterified cholesterol was not completely equilibrated within 2 h. Within 10 min after the injection of lipoproteins that had labeled free cholesterol, the bile contained labeled free cholesterol and within 20 min labeled bile acids. Both biliary cholesterol and bile acids initially were enriched 5-10-fold with the isotope that was originally contained in plasma HDL. Hepatic cholesterol was less enriched than bile cholesterol with the isotope of HDL. There was much less incorporation of radioactivity into biliary cholesterol and bile acids after the injection of [7(n)-3H]cholesteryl esters in HDL2 or HDL3 and [4-14C]cholesterol esters in LDL than after labeled free cholesterol, and there was little preference for cholesterol from one lipoprotein class. Although cholesteryl esters were equilibrated slowly between lipoprotein classes, their overall rate of removal from plasma was identical to that for the apolipoproteins of 125I-labeled LDL and 125I-labeled HDL during the first 2 h after injection. Labeled free cholesterol initially disappeared from the plasma compartment several times more rapidly than the esterified form or the lipoprotein apolipoprotein. Thus, cholesteryl esters probably interact with cells as part of intact lipoproteins, since they are not exchanged with cellular cholesterol like plasma free cholesterol.

Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents.

Cancer cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of cancer therapeutics is not fully defined. Current study concludes that DNA-damaging agents (etoposide and doxorubicin), ER stressor (thapsigargin), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including staurosporine, taxol, and sorafenib induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and p53-deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas inhibition of complex-II or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with wild type (WT) cells. Gross OXPHOS deficiencies promoted increased release of apoptosis-inducing factor from mitochondria compared with WT or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent doxorubicin showed strong binding to mitochondria, which was disrupted by complex-I-deficiency but not by complex-II-deficiency. Thapsigargin-induced caspase activation was reduced upon abrogation of complex-I or gross OXPHOS deficiency whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in cancer therapy.

Visible physical impairment and psychological adjustment among pediatric cancer survivors.

Because psychological and psychiatric assessments of childhood cancer survivors have revealed a high rate of psychiatric sequelae, the authors investigated the relationship between the degree of physical unpairment resulting from cancer treatment and the psychosocial adjustment problems of survivors. Ratings of physical impairment were based on the visibility of physical residua as well as the functional limitations they imposed. The results indicated that the psychosocial adjustment of survivors is not significantly related to the severity of physical impairment.

Intrathecal interferon in multiple sclerosis.

Human fibroblast interferon (IFN-beta) was administered by serial lumbar puncture to ten patients with multiple sclerosis (MS). Their clinical courses were compared with those of ten MS control patients who did not receive IFN-beta. As of this writing, the recipients have been followed up for 1.8 to 2.0 years (mean, 1.9 years), and the controls for 1.5 to 1.7 years (mean, 1.6 years). During the study, two recipients suffered four exacerbations, and six controls suffered 11 exacerbations. The recipients' rates of exacerbation during the study were significantly less than their rates both for the entire prestudy duration of the disease and for the 1.8 to 2.0 years immediately preceding entry into the study. The controls' rates of exacerbation before the study and during the study period did not differ significantly. Clinically, the conditions of five recipients and two controls improved, those of three recipients and four controls were unchanged, and those of two recipients and four controls worsened. Headaches, sometimes accompanied by fever and rarely by nausea and vomiting, occurred after injections of IFN-beta. Toxic symptoms usually disappeared within 24, hours; rarely, they persisted for seven to ten days. Each recipient had transient CSF pleocytosis and elevated levels to total protein (the latter remaining elevated in seven). These findings show that intrathecal administration of IFN-beta is feasible in patients with MS, warrant cautious optimism that intrathecal IFN-beta may be effective in altering the course of the disease, and support concepts of a viral or dysimmune cause of MS.

Intrathecal interferon in the treatment of multiple sclerosis. Patient follow-up.

Follow-up observations on patients with multiple sclerosis who were treated with human fibroblast interferon (interferon beta) administered intrathecally for six months revealed a persisting beneficial effect in terms of a reduction in exacerbation rates. At the time of our last report in 1982, ten interferon beta recipients had shown a reduction in their mean exacerbation rate from 1.8/yr before the study to 0.2/yr during the study while ten control patients with multiple sclerosis showed no change in their rates during the study (0.69/yr) compared with before it (0.68/yr). That report was based on observations made for means of 1.9 years in the recipients and 1.6 years in the controls. The recipient patients have now been followed up for 4.4 years (mean) and their exacerbation rates have continued to decrease to a current mean level of 0.16/yr. The control patients were "crossed over" and began receiving interferon beta intrathecally after they had been in the study for two years without showing any change in their rate. During the 2.0 years since crossover they also have shown a reduction in exacerbation rate to a mean of 0.30/yr. The toxic side effects of interferon beta administered intrathecally were acceptable in view of the benefit achieved. Interferon was identified in the cerebrospinal fluid (but not the serum) of two patients prior to treatment, which is probably a manifestation of de novo production of interferon by the central nervous system in response to the multiple sclerosis disease process.

Comparative effects of gemfibrozil and clofibrate in type III hyperlipoproteinemia.

Type III hyperlipoproteinemia (dysbetalipoproteinemia) is characterized by elevated concentrations of plasma cholesterol and triglycerides due to an increase in very low density lipoprotein (VLDL) remnant lipoproteins. In a retrospective analysis we observed that in 12 patients with this disorder, gemfibrozil reduced concentrations of total cholesterol, VLDL cholesterol and triglycerides by 48%, 72% and 68%, respectively. These changes were greater than those reported in a similar number of patients treated with clofibrate. Comparative data on the efficacy of different fibrates in this disorder are very limited; to assess this further we have compared the hypolipidemic effects of gemfibrozil (600 mg twice daily) and clofibrate (1 g twice daily) in six patients with well-characterized type III hyperlipoproteinemia. Baseline values were obtained after at least 8 weeks on diet and treatment values were obtained after 6 and 8 weeks of treatment with each drug. Treatment with clofibrate and gemfibrozil both resulted in significant reductions in the plasma concentrations of total cholesterol (40% and 54%), VLDL cholesterol (59% and 79%) and total triglycerides (48% and 70%), as well as a significant increase in HDL cholesterol (9% and 7%). Gemfibrozil was, however, significantly (P < 0.05) more effective in reducing plasma concentrations of total cholesterol, VLDL cholesterol and triglycerides than was clofibrate, in the same patients.

Metabolism of native and acetylated low density lipoproteins in squirrel monkeys with emphasis on aortas with varying severities of atherosclerosis.

We studied the clearance of 131I-labeled native low density lipoproteins (LDL) and 125I-acetyl LDL from the blood of hypercholesterolemic and atherosclerotic squirrel monkeys which had been fed a semipurified diet supplemented with cholesterol for 3 years and from control monkeys which had been fed the same diet without cholesterol. In agreement with previous observations in other species, acetyl LDL left the circulation much more rapidly than native LDL. The cholesterol supplemented monkeys removed native 131I-LDL to the liver, the major site of clearance of both LDL forms, more slowly than controls. The overall clearance of 125I-acetyl LDL was similar for the two groups. The aortic intima plus inner media (AIM) cleared both LDL forms much more slowly than other organs, and the ratio of acetyl LDL to native LDL cleared was quite high. The outer media (OM) showed less selectivity for acetyl LDL than the AIM. While LDL clearance by the OM was not affected by diet, the LDL clearance per g of AIM tissue was increased by 2-fold for both native and acetyl LDL in the cholesterol supplemented monkeys. These monkeys also had a 3-fold increase in AIM weight (due to intimal and subintimal thickening), which resulted in a 6-fold increase in the total LDL cleared by the AIM. The clearance of both LDL forms by the AIM correlated with three indices of atherosclerosis: intimal thickness, AIM weight, and AIM cholesterol concentration. The correlations were higher in the case of acetyl LDL clearance which may be due to the high affinity of the acetylated form for macrophages.