UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.

Antitumor efficacy of 90Y-NM600 targeted radionuclide therapy and PD-1 blockade is limited by regulatory T cells in murine prostate tumors.

BACKGROUND: Systemic radiation treatments that preferentially irradiate cancer cells over normal tissue, known as targeted radionuclide therapy (TRT), have shown significant potential for treating metastatic prostate cancer. Preclinical studies have demonstrated the ability of external beam radiation therapy (EBRT) to sensitize tumors to T cell checkpoint blockade. Combining TRT approaches with immunotherapy may be more feasible than combining with EBRT to treat widely metastatic disease, however the effects of TRT on the prostate tumor microenvironment alone and in combinfation with checkpoint blockade have not yet been studied. METHODS: C57BL/6 mice-bearing TRAMP-C1 tumors and FVB/NJ mice-bearing Myc-CaP tumors were treated with a single intravenous administration of either low-dose or high-dose 90Y-NM600 TRT, and with or without anti-PD-1 therapy. Groups of mice were followed for tumor growth while others were used for tissue collection and immunophenotyping of the tumors via flow cytometry. RESULTS: 90Y-NM600 TRT was safe at doses that elicited a moderate antitumor response. TRT had multiple effects on the tumor microenvironment including increasing CD8 +T cell infiltration, increasing checkpoint molecule expression on CD8 +T cells, and increasing PD-L1 expression on myeloid cells. However, PD-1 blockade with TRT treatment did not improve antitumor efficacy. Tregs remained functional up to 1 week following TRT, but CD8 +T cells were not, and the suppressive function of Tregs increased when anti-PD-1 was present in in vitro studies. The combination of anti-PD-1 and TRT was only effective in vivo when Tregs were depleted. CONCLUSIONS: Our data suggest that the combination of 90Y-NM600 TRT and PD-1 blockade therapy is ineffective in these prostate cancer models due to the activating effect of anti-PD-1 on Tregs. This finding underscores the importance of thorough understanding of the effects of TRT and immunotherapy combinations on the tumor immune microenvironment prior to clinical investigation.

[68 Ga]Ga-FAPI-46 PET for non-invasive detection of pulmonary fibrosis disease activity.

PURPOSE: The lack of effective molecular biomarkers to monitor idiopathic pulmonary fibrosis (IPF) activity or treatment response remains an unmet clinical need. Herein, we determined the utility of fibroblast activation protein inhibitor for positron emission tomography (FAPI PET) imaging in a mouse model of pulmonary fibrosis. METHODS: Pulmonary fibrosis was induced by intratracheal administration of bleomycin (1 U/kg) while intratracheal saline was administered to control mice. Subgroups from each cohort (n = 3-5) underwent dynamic 1 h PET/CT after intravenously injecting FAPI-46 radiolabeled with gallium-68 ([68 Ga]Ga-FAPI-46) at 7 days and 14 days following disease induction. Animals were sacrificed following imaging for ex vivo gamma counting and histologic correlation. [68 Ga]Ga-FAPI-46 uptake was quantified and reported as percent injected activity per cc (%IA/cc) or percent injected activity (%IA). Lung CT density in Hounsfield units (HU) was also correlated with histologic examinations of lung fibrosis. RESULTS: CT only detected differences in the fibrotic response at 14 days post-bleomycin administration. [68 Ga]Ga-FAPI-46 lung uptake was significantly higher in the bleomycin group than in control subjects at 7 days and 14 days. Significantly (P = 0.0012) increased [68 Ga]Ga-FAPI-46 lung uptake in the bleomycin groups at 14 days (1.01 ± 0.12%IA/cc) vs. 7 days (0.33 ± 0.09%IA/cc) at 60 min post-injection of the tracer was observed. These findings were consistent with an increase in both fibrinogenesis and FAP expression as seen in histology. CONCLUSION: CT was unable to assess disease activity in a murine model of IPF. Conversely, FAPI PET detected both the presence and activity of lung fibrogenesis, making it a promising tool for assessing early disease activity and evaluating the efficacy of therapeutic interventions in lung fibrosis patients.

The development of Nanosota-1 as anti-SARS-CoV-2 nanobody drug candidates.

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed that Nanosota-1 bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking viral receptor angiotensin-converting enzyme 2 (ACE2). The lead drug candidate possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD ~3000 times more tightly than ACE2 did and inhibited SARS-CoV-2 pseudovirus ~160 times more efficiently than ACE2 did. Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy against live SARS-CoV-2 infection in both hamster and mouse models. Unlike conventional antibodies, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-Fc documented an excellent in vivo stability and a high tissue bioavailability. As effective and inexpensive drug candidates, Nanosota-1 may contribute to the battle against COVID-19.

Low-dose targeted radionuclide therapy renders immunologically cold tumors responsive to immune checkpoint blockade.

Molecular and cellular effects of radiotherapy on tumor microenvironment (TME) can help prime and propagate antitumor immunity. We hypothesized that delivering radiation to all tumor sites could augment response to immunotherapies. We tested an approach to enhance response to immune checkpoint inhibitors (ICIs) by using targeted radionuclide therapy (TRT) to deliver radiation semiselectively to tumors. NM600, an alkylphosphocholine analog that preferentially accumulates in most tumor types, chelates a radioisotope and semiselectively delivers it to the TME for therapeutic or diagnostic applications. Using serial 86Y-NM600 positron emission tomography (PET) imaging, we estimated the dosimetry of 90Y-NM600 in immunologically cold syngeneic murine models that do not respond to ICIs alone. We observed strong therapeutic efficacy and reported optimal dose (2.5 to 5 gray) and sequence for 90Y-NM600 in combination with ICIs. After combined treatment, 45 to 66% of mice exhibited complete response and tumor-specific T cell memory, compared to 0% with 90Y-NM600 or ICI alone. This required expression of STING in tumor cells. Combined TRT and ICI activated production of proinflammatory cytokines in the TME, promoted tumor infiltration by and clonal expansion of CD8+ T cells, and reduced metastases. In mice bearing multiple tumors, combining TRT with moderate-dose (12 gray) external beam radiotherapy (EBRT) targeting a single tumor augmented response to ICIs compared to combination of ICIs with either TRT or EBRT alone. The safety of TRT was confirmed in a companion canine study. Low-dose TRT represents a translatable approach to promote response to ICIs for many tumor types, regardless of location.

A Synthetic Peptide CTL Vaccine Targeting Nucleocapsid Confers Protection from SARS-CoV-2 Challenge in Rhesus Macaques.

BACKGROUND: Persistent transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a COVID-19 pandemic. Several vaccines, conceived in 2020, that evoke protective spike antibody responses are being deployed in mass public health vaccination programs. Recent data suggests, however, that as sequence variation in the spike genome accumulates, some vaccines may lose efficacy. METHODS: Using a macaque model of SARS-CoV-2 infection, we tested the efficacy of a peptide-based vaccine targeting MHC class I epitopes on the SARS-CoV-2 nucleocapsid protein. We administered biodegradable microspheres with synthetic peptides and adjuvants to rhesus macaques. Unvaccinated control and vaccinated macaques were challenged with 1 × 108 TCID50 units of SARS-CoV-2, followed by assessment of clinical symptoms and viral load, chest radiographs, and sampling of peripheral blood and bronchoalveolar lavage (BAL) fluid for downstream analysis. RESULTS: Vaccinated animals were free of pneumonia-like infiltrates characteristic of SARS-CoV-2 infection and presented with lower viral loads relative to controls. Gene expression in cells collected from BAL samples of vaccinated macaques revealed a unique signature associated with enhanced development of adaptive immune responses relative to control macaques. CONCLUSIONS: We demonstrate that a room temperature stable peptide vaccine based on known immunogenic HLA class I bound CTL epitopes from the nucleocapsid protein can provide protection against SARS-CoV-2 infection in nonhuman primates.

The Development of a Novel Nanobody Therapeutic for SARS-CoV-2.

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a novel series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed that Nanosota-1 bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking out viral receptor ACE2. The lead drug possessing an Fc tag ( Nanosota-1C-Fc ) bound to SARS-CoV-2 RBD with a K d of 15.7picomolar (∼3000 times more tightly than ACE2 did) and inhibited SARS-CoV-2 infection with an ND 50 of 0.16microgram/milliliter (∼6000 times more potently than ACE2 did). Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy in hamsters subjected to SARS-CoV-2 infection. Unlike conventional antibody drugs, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-F c documented a greater than 10-day in vivo half-life efficacy and high tissue bioavailability. Nanosota-1C-Fc is a potentially effective and realistic solution to the COVID-19 pandemic. IMPACT STATEMENT: Potent and low-cost Nanosota-1 drugs block SARS-CoV-2 infections both in vitro and in vivo and act both preventively and therapeutically.

Anti-IL-6 Versus Anti-IL-6R Blocking Antibodies to Treat Acute Ebola Infection in BALB/c Mice: Potential Implications for Treating Cytokine Release Syndrome.

Cytokine release syndrome (CRS) is known to be a factor in morbidity and mortality associated with acute viral infections including those caused by filoviruses and coronaviruses. IL-6 has been implicated as a cytokine negatively associated with survival after filovirus and coronavirus infection. However, IL-6 has also been shown to be an important mediator of innate immunity and important for the host response to an acute viral infection. Clinical studies are now being conducted by various researchers to evaluate the possible role of IL-6 blockers to improve outcomes in critically ill patients with CRS. Most of these studies involve the use of anti-IL-6R monoclonal antibodies (α-IL-6R mAbs). We present data showing that direct neutralization of IL-6 with an α-IL-6 mAb in a BALB/c Ebolavirus (EBOV) challenge model produced a statistically significant improvement in outcome compared with controls when administered within the first 24 h of challenge and repeated every 72 h. A similar effect was seen in mice treated with the same dose of α-IL-6R mAb when the treatment was delayed 48 h post-challenge. These data suggest that direct neutralization of IL-6, early during the course of infection, may provide additional clinical benefits to IL-6 receptor blockade alone during treatment of patients with virus-induced CRS.

Pyronaridine tetraphosphate efficacy against Ebola virus infection in guinea pig.

The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to the shortage of available therapeutic options to treat patients infected with this or closely related viruses. We have recently computationally identified three molecules which have all demonstrated statistically significant efficacy in the mouse model of infection with mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial pyronaridine tetraphosphate (IC50 range of 0.82-1.30 µM against three strains of EBOV and IC50 range of 1.01-2.72 µM against two strains of Marburg virus (MARV)) which is an approved drug in the European Union and used in combination with artesunate. To date, no small molecule drugs have shown statistically significant efficacy in the guinea pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs directed us to a single 300 mg/kg or 600 mg/kg oral dose of pyronaridine 1hr after infection. Pyronaridine resulted in statistically significant survival of 40% at 300 mg/kg and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 mg/kg dosed once a day) had 43.5% survival. All animals in the vehicle treatment group succumbed to disease by study day 12 (100% mortality). The in vitro metabolism and metabolite identification of pyronaridine and another of our EBOV active molecules, tilorone, suggested significant species differences which may account for the efficacy or lack thereof, respectively in guinea pig. In summary, our studies with pyronaridine demonstrates its utility for repurposing as an antiviral against EBOV and MARV.

177Lu-NM600 Targeted Radionuclide Therapy Extends Survival in Syngeneic Murine Models of Triple-Negative Breast Cancer.

There is a clinically unmet need for effective treatments for triple-negative breast cancer (TNBC), as it remains the most aggressive subtype of breast cancer. Herein, we demonstrate a promising strategy using a tumor-targeting alkylphosphocholine (NM600) for targeted radionuclide therapy of TNBC. Methods: NM600 was radiolabeled with 86Y for PET imaging and 177Lu for targeted radionuclide therapy. 86Y-NM600 PET imaging was performed on female BALB/C mice bearing syngeneic 4T07 (nonmetastatic) and 4T1 (metastatic) TNBC tumor grafts (n = 3-5). Quantitative data derived from a PET-image region-of-interest analysis, which was corroborated by ex vivo biodistribution, were used to estimate the dosimetry of 177Lu-NM600 treatments. Weight measurement, complete blood counts, and histopathology analysis were performed to determine 177Lu-NM600 toxicity in naïve BALB/C mice administered 9.25 or 18.5 MBq. Groups of mice bearing 4T07 or 4T1 grafts (n = 5-6) received excipient or 9.25 or 18.5 MBq of 177Lu-NM600 as a single or fractionated schedule, and tumor growth and overall survival were monitored. Results: Excellent tumor targeting and rapid normal-tissue clearance of 86Y-NM600 were noted in both 4T07 and 4T1 murine models. Ex vivo biodistribution corroborated the accuracy of the PET data and validated 86Y-NM600 as a surrogate for 177Lu-NM600. 177Lu-NM600 dosimetry showed absorbed doses of 2.04 ± 0.32 and 1.68 ± 0.06 Gy/MBq to 4T07 and 4T1 tumors, respectively, which were larger than those delivered to liver (1.28 ± 0.09 Gy/MBq) and to bone marrow (0.31 ± 0.05 Gy/MBq). The 177Lu-NM600 injected activities used for treatment were well tolerated and resulted in significant tumor growth inhibition and prolonged overall survival in both tested TNBC models. A complete response was attained in 60% of treated mice bearing 4T07 grafts. Conclusion: Overall, our results suggest that 177Lu-NM600 targeted radionuclide therapy has potential for TNBC and merits further exploration in a clinical setting.

Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection.

Recent outbreaks of the Ebola virus (EBOV) have focused attention on the dire need for antivirals to treat these patients. We identified pyronaridine tetraphosphate as a potential candidate as it is an approved drug in the European Union which is currently used in combination with artesunate as a treatment for malaria (EC50 between 420 nM-1.14 µM against EBOV in HeLa cells). Range-finding studies in mice directed us to a single 75 mg/kg i.p. dose 1 hr after infection which resulted in 100% survival and statistically significantly reduced viremia at study day 3 from a lethal challenge with mouse-adapted EBOV (maEBOV). Further, an EBOV window study suggested we could dose pyronaridine 2 or 24 hrs post-exposure to result in similar efficacy. Analysis of cytokine and chemokine panels suggests that pyronaridine may act as an immunomodulator during an EBOV infection. Our studies with pyronaridine clearly demonstrate potential utility for its repurposing as an antiviral against EBOV and merits further study in larger animal models with the added benefit of already being used as a treatment against malaria.

90Y-NM600 targeted radionuclide therapy induces immunologic memory in syngeneic models of T-cell Non-Hodgkin's Lymphoma.

Finding improved therapeutic strategies against T-cell Non-Hodgkin's Lymphoma (NHL) remains an unmet clinical need. We implemented a theranostic approach employing a tumor-targeting alkylphosphocholine (NM600) radiolabeled with 86Y for positron emission tomography (PET) imaging and 90Y for targeted radionuclide therapy (TRT) of T-cell NHL. PET imaging and biodistribution performed in mouse models of T-cell NHL showed in vivo selective tumor uptake and retention of 86Y-NM600. An initial toxicity assessment examining complete blood counts, blood chemistry, and histopathology of major organs established 90Y-NM600 safety. Mice bearing T-cell NHL tumors treated with 90Y-NM600 experienced tumor growth inhibition, extended survival, and a high degree of cure with immune memory toward tumor reestablishment. 90Y-NM600 treatment was also effective against disseminated tumors, improving survival and cure rates. Finally, we observed a key role for the adaptive immune system in potentiating a durable anti-tumor response to TRT, especially in the presence of microscopic disease.

Multiphase multi-detector row computed tomography in the setting of chronic liver disease and orthotopic liver transplantation: can a series be eliminated in order to reduce radiation dose?

OBJECTIVE: The objectives of this study were to explore utilization of multi-detector row computed tomography (MDCT) in screening for hepatocellular carcinoma (HCC) and to modify a liver CT protocol with a goal of dose reduction. METHODS: An electronic mail survey querying HCC surveillance practices was sent. One hundred forty consecutive patients referred for HCC indications underwent 4-phase MDCT of the liver. The unenhanced and delayed phases were evaluated by 3 readers for identification of HCC and reader confidence. The estimated effective dose (ED) was calculated. RESULTS: Computed tomography is primarily used to screen for HCC. Average estimated ED was 35.5 mSv. Unenhanced phase did not add to reader confidence; delayed phase increased confidence in 47% of cases. Thirty-two percent of the screening population had cumulative ED of greater than 200 mSv. CONCLUSIONS: Multi-detector row CT of the liver is used frequently in screening for HCC. Unenhanced phase imaging does not add to HCC detection and may be eliminated to reduce radiation dose.

Effect of force on alveolar bone surrounding miniscrew implants: a 3-dimensional microcomputed tomography study.

INTRODUCTION: The primary aim of this study was to better understand how bone adapts to forces applied to miniscrew implants. A secondary aim was to determine whether the direction of force applied to miniscrew implants has an effect on bone surrounding the miniscrew implants. METHODS: A randomized split-mouth design, applied to 6 skeletally mature male foxhound dogs, was used to compare miniscrew implants loaded for 9 weeks with 200 or 600 g to unloaded control miniscrew implants. By using microcomputed tomography, with an isotropic resolution of 6 µm, bone volume fractions (bone volume/total volume) were calculated for bone around the entire miniscrew implant surface. Bone volume fractions were calculated for bone 6 to 24, 24 to 42, and 42 to 60 µm from the miniscrew implant surface. For each loaded miniscrew implant, the bone volume fraction was also calculated for 2 compression and 2 noncompression zones. RESULTS: The 6 to 24-µm layer showed a significantly lower (P <0.05) bone volume fraction than did the 24 to 42-µm and the 42 to 60-µm layers, which were not significantly different. The bone volume fractions of cortical bone surrounding the apical aspects of the unloaded miniscrew implants were significantly greater (P <0.05) than the bone volume fractions of cortical bone surrounding the loaded miniscrew implants. In contrast, the bone volume fractions of noncortical bone surrounding loaded miniscrew implants were significantly greater (P <0.05) than the bone volume fractions of bone surrounding the unloaded miniscrew implants. Miniscrew implants loaded with 200 g showed significantly greater (P <0.05) amounts of noncortical bone volume fractions than did miniscrew implants loaded with 600 g. With both 200 and 600 g, zones under compression had significantly greater bone volume fractions than did the noncompression zones. CONCLUSIONS: The application of force, the amount of force applied, and the direction of force all have significant effects on the amounts of bone produced around miniscrew implants.

Effects of aging and degeneration on the human intervertebral disc during the diurnal cycle: a finite element study.

A significant biochemical change that takes place in intervertebral disc degeneration is the loss of proteoglycans in the nucleus pulposus. Proteoglycans attract fluid, which works to reduce mechanical stresses in the solid matrix of the nucleus and provide a hydrostatic pressure to the annulus fibrosus, whose fibrous nature accommodates this stress. Our goals are to develop an osmo-poroelastic finite element model to study the relationship between proteoglycan content and the stress distribution within the disc and to analyze the effects of degeneration on the disc's diurnal mechanical response. Stress in the annulus increased with degeneration from ∼0.2 to 0.4 MPa, and an increase occurred in the center of the nucleus from 1.2 to 1.6 MPa. The osmotic pressure in the central nucleus region decreased the most with degeneration, from ∼0.42 to ∼0.1 MPa in a severely dehydrated disc. A 3% decrease in diurnal fluid lost with degeneration equated to ∼21% decrease in fluid exchange, and hence a decrease in nutrients that require convection to enter the disc. We quantified the increases in internal stresses in the nucleus and annulus throughout the various stages of degeneration, suggesting that these changes lead to further remodeling of the tissue.

Respiratory-triggered three-dimensional T2-weighted MR cholangiography after injection of gadoxetate disodium: is it still reliable?

PURPOSE: To test the null hypothesis that there is no quantitative or qualitative difference between respiratory-triggered three-dimensional (3D) T2-weighted magnetic resonance (MR) cholangiography performed before or after administration of gadoxetate disodium. MATERIALS AND METHODS: For this retrospective HIPAA-compliant dual-center study, institutional review board approval was obtained, and a waiver of informed consent was granted. Between July and December 2008, 60 patients (age range, 18-82 years) who were referred for liver MR imaging with gadoxetate disodium underwent respiratory-triggered 3D MR cholangiography before and immediately after completion of portal venous phase contrast material-enhanced T1-weighted MR imaging. Quantitative signal-to-noise ratio (SNR) measurements were obtained in the extrahepatic biliary tract in both MR cholangiographic data sets in each patient. Qualitative assessment was performed by four readers with a four-point scale to assess the depiction of extra- and intrahepatic ducts up to the third order. Statistical analysis consisted of a one-sided Wilcoxon signed rank test, with a P value of less than .05 indicating a significant difference. RESULTS: There was a significant decrease in mean SNR in the MR cholangiographic data set after injection of gadoxetate disodium. SNR was 96 + or - 50 [standard deviation] and 78 + or - 47 before and after contrast media administration, respectively (P < .0001). For all readers, qualitative differences were most obvious in the depiction of the common bile duct and second- and third-order biliary branches, with the precontrast MR cholangiographic data sets being preferred (P < .0001). Precontrast data sets were also significantly preferred in the assessment of the right and left hepatic ducts by all readers. CONCLUSION: Gadoxetate disodium adversely affects respiratory-triggered 3D MR cholangiography, both qualitatively and quantitatively. We recommend that such a sequence be performed before injection of gadoxetate disodium.

The effect of nucleus implant parameters on the compressive mechanics of the lumbar intervertebral disc: a finite element study.

A simplified finite element model of the human lumbar intervertebral disc was utilized for understanding nucleus pulposus implant mechanics. The model was used to assess the effect of nucleus implant parameter variations on the resulting compressive biomechanics of the lumbar anterior column unit. The effects of nucleus implant material (modulus and Poisson's ratio) and geometrical (height and diameter) parameters on the mechanical behavior of the disc were investigated. The model predicted that variations in implant modulus contribute less to the compressive disc mechanics compared to the implant geometrical parameters, for the ranges examined. It was concluded that some threshold exists for the nucleus implant modulus, below which little variations in load-displacement behavior were shown. Compressive biomechanics were highly affected by implant volume (under-filling the nucleus cavity, line-to-line fit, or over-filling the nucleus cavity) with a greater restoration of compressive mechanics observed with the over-filled implant design. This work indicated the effect of nucleus implant parameter variations on the compressive mechanics of the human lumbar intervertebral disc and importance of the "fit and fill" effect of the nuclear cavity in the restoration of the human intervertebral disc mechanics in compression. These findings may have clinical significance for nucleus implant design.

Acute ethanol toxicity from ingesting mouthwash in children younger than age 6, 1989-2003.

PURPOSE: The purpose of this study was to analyze American Association of Poison Control Centers (AAPCC) reports of suspected overingestion of mouthwash by children under age 6 and examine the effect of a 1995 Consumer Product Safety Commission (CPSC) rule requiring child-resistant packaging for mouthwashes containing at least 3 g (0.11 oz) of ethanol per package. METHODS: The volume of ethanol ingested per kg of body weight was computed for children at the 5th, 50th, and 95th percentiles. The potentially toxic and potentially lethal volumes of 100% ethanol at each weight were also determined. The authors used segmented regression to test the difference in slopes between 1989 to 1996 (preintervention) and 1996 to 2003 (postintervention). RESULTS: Incidence of overingestion rose from a low of 12.7 per 100,000 (1991) to 20.7 (1996). The increase ended with the adoption of the CPSC rule, declining to 16.8 per 100,000 in 2001 and rising to 17.9 in 2003. CONCLUSIONS: This study's analysis suggests that the CPSC rule requiring child-resistant packaging on containers of mouthwash containing 3 g or more of ethanol has been successful in reducing AAPCC's reports of mouthwash overingestion. Health care providers should take a more active role by informing parents of the dangers associated with accidental ingestion of ethanol-containing mouthwash. Manufacturers should print warnings about the potential hazard of high ethanol concentrations on labels more prominent and they should stop producing mouthwashes with such high concentrations of ethanol. Moreover, they should also consider discontinuing packaging mouthwash in large containers.

Hidden morbidity with "successful" early discharge.

OBJECTIVE: This study was conducted to determine if early postnatal discharge (EDC; < or =48 hours) in well newborns had an effect on the rate of hospital readmission within the first week after hospital discharge when compared to infants who remained >48 hours after birth (later discharge, LDC). STUDY DESIGN: This was a retrospective medical chart review. Charts of infants born between January 1994 and December 1998, discharged as "well newborns" and treated subsequently at a primary children's hospital within 7 days of neonatal discharge, were reviewed. Infants were categorized by length of neonatal hospital stay, level of medical intervention (emergency department treatment or hospital admission), and final diagnosis. RESULTS: There was a significant increase in hospital readmission rate for LDC infants when compared to EDC infants. When considering jaundice alone as an admitting diagnosis, EDC infants were admitted at a higher rate than LDC infants and with higher serum bilirubin concentrations. Readmitted, jaundiced infants had been almost always breast-fed. CONCLUSION: Overall, EDC of well newborns appears to be a safe and reasonable practice. However, the risk for severe jaundice is an unresolved issue that requires a discharge strategy and early follow-up to prevent serious morbidity.