Machine learning and statistical prediction of fastball velocity with biomechanical predictors.

In recent years, one of the most important factors for success among baseball pitchers is fastball velocity. The purpose of this study was to (1) to develop statistical and machine learning models of fastball velocity, (2) to identify the strongest predictors of fastball velocity, and (3) to compare the models' prediction performances. Three dimensional biomechanical analyses were performed on high school (n = 165) and college (n = 62) baseball pitchers. A total of 16 kinetic and kinematic predictors from the entire pitching sequence were included in regression and machine learning models. All models were internally validated through ten-fold cross-validation. Model performance was evaluated through root mean square error (RMSE) and calibration with 95% confidence intervals. Gradient boosting machines demonstrated the best prediction performance [RMSE: 0.34; Calibration: 1.00 (95% CI: 0.999, 1.001)], while regression demonstrated the greatest prediction error [RMSE: 2.49; Calibration: 1.00 (95% CI: 0.85, 1.15)]. Maximum elbow extension velocity (relative influence: 19.3%), maximum humeral rotation velocity (9.6%), maximum lead leg ground reaction force resultant (9.1%), trunk forward flexion at release (7.9%), time difference of maximum pelvis rotation velocity and maximum trunk rotation velocity (7.8%) demonstrated the greatest influence on pitch velocity. Gradient boosting machines demonstrated better calibration and reduced RMSE compared to regression. The influence of lead leg ground reaction force resultant and trunk and arm kinematics on pitch velocity demonstrates the interdependent relationship of the entire kinetic chain during the pitching motion. Coaches, players, and performance professionals should focus on the identified metrics when designing pitch velocity improvement programs.

Verification of High-Rate Vertical Loading Laboratory Skeletal Fractures by Comparison with Theater Injury Patterns.

For the current study, an existing theater injury data set was compared to component and whole body experiments meant to replicate the theater high rate vertical loading environment. The theater injury data set was derived from real world events that were within the design range of the Warrior Injury Assessment Manikin. A qualitative and quantitative assessment of the whole body fracture patterns was developed to determine whether the laboratory loading was correctly representing the resulting injuries seen in theater Underbody Blast (UBB) events. Results indicated that most of the experimental test fracture patterns were similar to the theater injuries for Abbreviated Injury Scale body regions of interest (lower extremities, pelvis, and spine); however, some of the body regions had higher similarity scores compared to others. Whole body fracture distribution was less similar than the component tests because of differences in injury distributions. The lower extremity whole body similarity was lower than spine and pelvis similarity. This analysis was able to identify some experimental tests that might not represent theater loading. In conclusion, this analysis confirmed that some laboratory testing produced skeletal injury patterns that are seen in comparable theater UBB events.

Clinical, metabolic, and molecular genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in 30 dogs.

Genotype-phenotype correlations of humans and dogs with hereditary methemoglobinemia are not yet well characterized. We determined total hemoglobin and methemoglobin (MetHb) concentrations, cytochrome b5 reductase (CYB5R) enzyme activities, genotypes, and clinical signs in 30 dogs with persistent cyanosis without cardiopulmonary disease. Erythrocytic CYB5R enzyme activities were low in all dogs assayed. Owner-reported quality of life ranged from subclinical to occasional exertional syncope. Two previously reported and two novel CYB5R3 missense variants were identified among the methemoglobinemic cohort and were predicted to impair enzyme function. Two variants were recurrent: a homozygous Ile194Leu substitution was found in Pomeranians and other small dogs, and a homozygous Arg219Pro change occurred predominately in pit bull terriers. The other two variants were Thr202Ala and Gly76Ser substitutions in single dogs. Of the two common CYB5R3 genotypes, Arg219Pro was associated with a more severe metabolic phenotype. We conclude that CYB5R3 deficiency is the predominate cause of canine hereditary methemoglobinemia. Although this finding is unlikely to alter the clinical approach to hereditary methemoglobinemia in dogs, it demonstrates the possibility of how genotype-phenotype cohort analysis might facilitate precision medicine in the future in veterinary medicine.

Epidemiological profile of pain and non-steroid anti-inflammatory drug use in collegiate athletes in the United States.

BACKGROUND: Although athletic endeavours are associated with a high amount of physical stress and injury, the prevalence of pain is underreported in the sports medicine literature with only a few studies reporting pain on collegiate athletes or exploring sex difference of pain. Impact of pain on athlete availability, training and performance can be mitigated when key epidemiological information is used to inform adequate pain management strategies. This study aims to 1) provide an epidemiological profile of self-reported pain experienced by the National Collegiate Athletic Association (NCAA) athletes by sex during the first half of the 2019 season, 2) describe their self-reported non-steroidal anti-inflammatory drug (NSAID) use. METHODS: Online survey was completed by athletes at three NCAA institutions from 1 August to 30 September 2019. Descriptive statistics were used to describe player demographic data, self-reported pain and self-reported NSAID use. Pain incidence proportion were calculated. RESULTS: Two hundred thirty female athletes and 83 male athletes completed the survey. Self-reported pain incidence proportion for female athletes was 45.0 (95% CI 41.5-48.5) vs 34.9 (95% CI 29.4-40.4) for male athletes. Majority of the athletes did not report pain (55% female vs 62% male) during the first half of the 2019 season. Female athletes reported pain in their back (35%), knee (26%), and ankle/foot (23%) whilst male athletes reported pain in their knee (35%), back (28%), and shoulder (24%). Of all athletes, 28% female vs 20% male athletes reported currently taking NSAIDs. Of athletes that reported pain, 46% female vs 38% male athletes currently took NSAIDs. 70% female vs 61% male athletes self-purchased NSAIDs, and 40% female vs 55% male athletes consumed alcohol. CONCLUSIONS: Half of female athletes and one in three male athletes reported pain. Most commonly back, knee and foot/ankle pain and knee, back and shoulder pain was reported in female and male athletes respectively. One in four female athletes and one in five male athletes use NSAIDs for pain or prophylactic purpose. Majority self-purchase these medications indicating need for health literacy interventions to mitigate potential adverse effects.

A homozygous ADAMTS2 nonsense mutation in a Doberman Pinscher dog with Ehlers Danlos syndrome and extreme skin fragility.

An eight-week old Doberman Pinscher was diagnosed with Ehlers Danlos syndrome based on the dog's hyper-mobile carpal, tarsal and stifle joints and abnormal skin. The skin was loose and hyper-elastic with several wounds and large atrophic scars. The dog was euthanized after a severe degloving injury from minimal trauma. A whole-genome sequence, generated with DNA from the dog's blood, contained a rare, homozygous C-to-T transition at position 2408978 on chromosome 11. This transition is predicted to alter the ADAMTS2 transcript (ADAMTS2:c.769C>T) and encode a nonsense mutation (p.Arg257Ter). Biallelic ADAMTS2 mutations have caused a type of Ehlers Danlos syndrome known as dermatosparaxis in other species.

Azithromycin Fails to Prevent Accelerated Airway Obliteration in T-bet-/- Mouse Lung Allograft Recipients.

BACKGROUND: Cellular and molecular mechanisms of acute and chronic lung allograft rejection have yet to be clearly defined, and obliterative bronchiolitis (OB) remains the primary limitation to survival in lung transplant recipients (LTRs). We have previously shown that T-bet-deficient recipients of full major histocompatibility complex (MHC)-mismatched, orthotopic left lung transplants develop accelerated obliterative airway disease (OAD) in the setting of acute cellular rejection characterized by robust alloimmune CD8+ interleukin (IL)-17 and interferon (IFN)-γ responses that are attenuated with neutralization of IL-17. Azithromycin has been shown to be beneficial in some LTRs with bronchiolitis obliterans syndrome/OB. Here, we evaluated the effects of azithromycin on rejection pathology and T-cell effector responses in T-bet-/- recipients of lung transplants. METHODS: Orthotopic left lung transplantation was performed in BALB/c → B6 wild type or BALB/c → B6 T-bet-/- strain combinations as previously described. Mice treated with azithromycin received 10 mg/kg or 50 mg/kg subcutaneously daily. Lung allograft histopathology was analyzed at day 10 or day 21 post-transplantation, and neutrophil staining for quantification was performed using anti-myeloperoxidase. Allograft mononuclear cells were isolated at day 10 for T-cell effector cytokine response assessment using flow cytometry. RESULTS: We show that while azithromycin significantly decreases lung allograft neutrophilia and CXCL1 levels and attenuates allospecific CD8+ IL-17 responses early post-transplantation, OAD persists in T-bet-deficient mice. CONCLUSIONS: Our results indicate that lung allograft neutrophilia is not essential for the development of OAD in this model and suggest allospecific T-cell responses that remain despite marked attenuation of CD8+ IL-17 are sufficient for obliterative airway inflammation and fibrosis.

Post-transplant lymphoproliferative disorders are not associated with IgG4 sclerosing disease.

BACKGROUND: Although the majority of post-transplant lymphoproliferative disorder (PTLD) cases are associated with Epstein-Barr virus (EBV), 20-42% of cases are EBV negative (EBV-N). The antigenic stimulus that drives EBV-N PTLD is unknown, but is likely heterogeneous. A common feature of PTLD, regardless of EBV status, is an abnormal polytypic lymphoplasmacytic infiltrate. Immunglobulin-G4 (IgG4) syndrome is also characterized by a polytypic lymphoplasmacytic infiltrate with a predominance of IgG4-positive (IgG4-P) plasma cells. METHODS: We investigated the possibility of an association between EBV-N PTLD and IgG4 syndrome. Of 33 evaluated PTLD cases, 9 (27%) were EBV-N. EBV-N PTLD cases showed longer transplantation-to-diagnosis times than EBV-positive cases. RESULTS: A single patient had a preceding benign duodenal biopsy with focally prominent IgG4-P plasma cells; however, no clinical data supported IgG4 syndrome, precluding an association between IgG4 syndrome and subsequent EBV-N PTLD in this patient. CONCLUSION: As none of 29 evaluable cases of PTLD (including all 9 EBV-N cases) were associated with an increase in IgG4-P plasma cells, IgG4 syndrome does not appear to play a role in the etiology of EBV-N PTLD. The significance of these findings and the current understanding of the etiology of EBV-N PTLD are discussed.

Novel techniques for enhancing sensitivity in static headspace extraction-gas chromatography.

Static headspace extraction-gas chromatography (SHE-GC) is one of the most commonly used techniques for the analysis of volatile compounds. It is considered by most to be a mature technique and to an extent this is true: there are many users from outside the traditional chromatography research community developing and publishing SHE-GC methods and there are numerous instruments and devices for SHE-GC commercially available. However, research on new SHE-GC methods continues. In this review, several interesting new developments in SHE-GC are described using examples from the past three years' literature. First, the fundamental theory of SHE-GC is reviewed to provide a basis and common theme for the discussion of new methods. Next, several areas of SHE-GC research are explored: new sampling configurations, analyte derivatization and ionic liquids as solvents. These are all means for enhancing partitioning of the analyte into the vapor phase, thus improving analytical sensitivity of the overall SHE-GC method. Ideally, partitioning of analytes into the vapor phase is increased while partitioning of matrix components is not, or is decreased. There are many aspects of the seemingly straightforward process in SHE-GC that require further fundamental research to extend the application range of SHE-GC and to make method development more systematic.

The fate of chlorine and organic materials in swimming pools.

The fate of organic nitrogen and carbon introduced into a swimming pool by pool users has been studied using a 2.2 m(3) model pool. The study made use of a body fluid analogue (BFA), containing the primary endogenous organic amino compounds, and a soiling analogue represented by humic acid (HA). The system was used to examine the effect of organic loading and organic carbon (OC) sources (i.e. amino or HA) on the levels and speciation of the key chlorinated disinfection by-products of trihalomethanes (THMs) and chloramines under operating conditions representative of those employed on a full-scale pool. Results revealed OC, chloramines and THMs to all attain steady-state levels after 200-500 h of operation, reflecting mineralisation of the dosed OC. Steady-state levels of OC were roughly linearly dependent on dose rate over the range of operational conditions investigated and, as with the chloramine levels recorded, were in reasonable agreement with those reported for full-scale pools. THM levels recorded were somewhat lower than those found in real pools, and were dependent on both on pH carbon source: the THM formation propensity for the soling analogue was around eight times than of the BFA. Of the assayed by-products, only nitrate was found to accumulate, accounting for 4-28% of the dosed amino nitrogen. Contrary to previous postulations based on the application of Henry's Law, only insignificant amounts of the volatile by-products were found to be lost to the atmosphere.

Growth stimulatory angiotensin II type-1 receptor is upregulated in breast hyperplasia and in situ carcinoma but not in invasive carcinoma.

Two different receptors which bind angiotensin II specifically have been identified in humans and were designated angiotensin II type-1 receptor (AT1) and angiotensin II type-2 receptor (AT2). They only have 34% sequence homology and act through different signalling pathways. AT1 stimulation has been implicated in hypertrophy and hyperplasia in various tissues. In order to study the involvement of AT1 in tissues from controls (n=10) and patients with hyperplasia (n=33), ductal carcinoma in situ (DCIS) (n=23) and invasive carcinoma of the breast (n=25), we tested biopsies and breast-derived cell lines using immunocytochemistry, in situ hybridisation and cell proliferation techniques. The results show specific overexpression of AT1 receptor on the cytoplasmic membrane of cells of hyperplastic lesions with and without atypia and on DCIS of the breast. Evidence for growth stimulation is provided by in vitro experiments showing growth induction by angiotensin II of T47D cells which express the AT1 but not the AT2 receptor. The expression of AT1 on the cell membrane disappears in invasive breast cancer cells suggesting a regulatory pathway which is no longer needed in invasive carcinoma. The specific AT1 expression upregulation might well be an important step in the pathogenesis of hyperplasia of the breast, which is regarded as a precursor lesion for breast cancer.

Effect of the R1 element on expression of the US3 and US6 immune evasion genes of human cytomegalovirus.

Human cytomegalovirus (HCMV) has several gene products that are important for escape from immune surveillance. These viral gene products downregulate the expression of HLA molecules on the cell surface. The viral US3 and US6 gene products are expressed at immediate-early and early times after infection, respectively. There are two regulatory regions between the US3 and the US6 transcription units. The first region is an NF-kappaB responsive enhancer that promotes the immediate-early expression of the US3 gene and is designated the R2 enhancer. Upstream of the R2 enhancer is a region designated the R1 element that in transient transfection assays behaves as a silencer by repressing the effect of the enhancer on downstream gene expression (A. R. Thrower et al., J. Virol. 1996, 70, 91; Y.-J. Chan et al., J. Virol. 1996, 70, 5312). We constructed recombinant viruses with wild-type or mutated R1 elements. The expression of the US3 gene at 6 h after infection and the US6 gene at 24 h was higher when the R1 element was present. The R1 element in the context of the viral genome is not a silencer of US3 or US6 gene expression. The R1 element has multiple effects on the US3 and US6 RNAs. It enhances the level of US3 and US6 mRNA; it determines the 3'-end cleavage and polyadenylation of US6 RNA, and it stabilizes read-through viral RNAs. The potential mechanisms of R1 enhancement of US3 and US6 gene expression are discussed.

Distribution of type-1 and type-2 angiotensin receptors in the normal human lung and in lungs from patients with chronic obstructive pulmonary disease.

This study was designed to examine the cellular distribution of the angiotensin II type-1 (AT1) and type-2 (AT2) receptors in the normal human and pathological human lung. Riboprobes were prepared against specific portions of each receptor DNA and labelled with FITC for detection using an anti-FITC antibody in combination with the alkaline phosphatase-anti-alkaline phosphatase technique and new Fuchsin. These were used to detect the presence of receptor mRNA in the lung. Specific antibodies were used to detect receptor protein in cells by immunocytochemistry. Image analysis was used in order to semi-quantify receptor density. AT1 receptor mRNA and protein were localised on vascular smooth muscle cells, macrophages and in the stroma underlying the airways epithelium probably relating to underlying fibroblasts. The AT1 receptor protein was not expressed in the epithelium although there was a low level of mRNA. In contrast, AT2 receptor RNA and protein was observed in the epithelium, with strong staining on the bronchial epithelial cell brush border and also on many of the underlying mucous glands. The AT2 receptor was also present on some endothelial cells. These findings were supported by the presence of mRNA in each case. In patients with chronic obstructive pulmonary disease, there was a five- to sixfold increase in the ratio of AT1 to AT2 receptors in the regions of marked fibrosis surrounding the bronchioles. This correlated well with the reduced lung function as expressed by the forced expiratory volume.

A randomized controlled trial on the effect of educational interventions in promoting airway management skill maintenance.

STUDY OBJECTIVE: This study was conducted to determine the natural history of airway management skill decay and examine the effect of independent practice and periodic feedback on airway management skill maintenance. METHODS: This prospective, randomized controlled study conducted at Dalhousie University in Halifax, Nova Scotia, Canada, between November 1997 and September 1998. A convenience sample of 84 health sciences students with no prior airway management experience was used. Participants were trained using an advanced airway manikin and then were randomly assigned to control (n=24), periodic feedback only (n=30), and independent practice plus periodic feedback (n=30) groups. Performance was measured by a 52-point weighted checklist at 0, 16, 25, and 40 weeks after the initial program. RESULTS: Group scores were analyzed using a mixed-model repeated-measures analysis of variance and Bonferroni-adjusted P values. Overall group (P =.0002) and time (P =.0001) effects were significant. At time 0, there was no statistical difference in mean scores between groups (range 45.0 to 45.2). Control group performance fell over the first time interval (0 to 16 weeks) (mean score=34.0, P =.002) and remained lower at all intervals without further significant change. Scores in the independent practice plus feedback group revealed no significant changes over time and were significantly higher than the control group throughout. Performance in the periodic feedback only group showed a nonsignificant trend to improved performance over the control group. CONCLUSION: Airway management skill performance declines early after initial training. Independent practice combined with periodic feedback was effective in maintaining performance scores in an advanced airway management simulation. Periodic evaluation with feedback alone showed a nonsignificant trend toward improvement over control.

Focal up-regulation of E-cadherin-catenin complex in inflamed bowel mucosa but reduced expression in ulcer-associated cell lineage.

The E-cadherin-catenin complex is important for the maintenance of epithelial architecture. We studied its expression in Crohn disease, ulcerative colitis, acute ileitis, and controls. Immunohistochemical stainings for E-cadherin, alpha-catenin, beta-catenin and gamma-catenin were performed. E-cadherin messenger RNA (mRNA) was detected using riboprobes. In active inflammation, there was up-regulation of the complex. In particular, epithelium adjacent to ulcers showed increased expression of protein and mRNA, but in ulcer-associated cell lineage, the intensity of staining was weak to negative. In focal inflammation, up-regulation was found in affected areas. Reparative epithelium growing over denuded areas showed weaker expression. Since structural or functional perturbation in any of the molecules of the E-cadherin-catenin complex results in loss of intercellular adhesion, the preexistent epithelium may benefit from up-regulation to try to maintain its normal architecture under inflammatory conditions. Reduced expression in reparative epithelium and ulcer-associated cell lineage could facilitate the motility of these cells.

Sensitization to inhaled antigen by intratracheal instillation of dendritic cells.

BACKGROUND: Airway dendritic cells (DCs) capture and present inhaled antigen. It is not known whether antigen presentation by DCs in the airways is sufficient to induce sensitization to inhaled antigen in vivo. METHODS: Rats were immunized by intratracheal instillation of ovalbumin (OVA) -pulsed bone marrow-derived DCs or macrophages and exposed 10 days later to a 30-min aerosol of OVA on 3 consecutive days. Total and differential cell counts and flow cytometry on bronchoalveolar lavage (BAL) fluid, airway histology and serum OVA-immunoglobulin (Ig) E levels were analysed 24 h after the last exposure. RESULTS: As few as 2 x 104 OVA-DC induced sensitization to inhaled OVA. The secondary response to OVA-aerosol consisted of an antigen-specific increase in the number of bronchoalveolar mononuclear cells, activated CD4-positive alphabeta-TCR T lymphocytes, neutrophils and few eosinophils. Peribronchial and perivascular mononuclear cell infiltrates were seen on histological analysis. There was no production of systemic OVA-IgE. Bone marrow-derived macrophages did not induce sensitization. CONCLUSION: Delivering antigen to the respiratory tract via professional antigen-presenting DCs sensitizes for a secondary response to inhaled antigen leading to airway inflammation. This model will prove very useful for studying the early events of sensitization to inhaled antigen using the respiratory route.

Presence of substance P and neurokinin 1 receptors in human sputum macrophages and U-937 cells.

Tachykinins such as substance P (SP) may be involved in the pathogenesis of inflammatory airway diseases such as asthma. This study investigated the presence of SP and its receptor in the differentiated macrophage-like U-937 cell line and in macrophages from sputum induced in healthy subjects (n=8). In situ hybridization with digoxigenin-labelled sense and antisense complementary ribonucleic acid (cRNA) probes was used to determine the expression of SP and its receptor (neurokinin (NK)1 receptor). SP-immunoreactive material was detected using a rabbit anti-SP antiserum and the alkaline phosphatase anti-alkaline phosphatase technique. Beta-preprotachykinin (PPT)-I messenger ribonucleic acid (mRNA) encoding SP, was detected using in situ hybridization in differentiated U-937 cells as well as in CD45+ human leukocyte antigen (HLA) DR+ sputum macrophages. The expression of the beta-PPT-I mRNA was increased in lipopolysaccharide (LPS)-stimulated U-937 cells. SP-immunoreactive material was found in differentiated U-937 cells and in CD68+ sputum macrophages. NK1 receptor mRNA was detected in differentiated U-937 cells and sputum macrophages. Incubation of U-937 cells with SP considerably increased the expression of NK1 receptor mRNA. This study demonstrates that human monocytes/macrophages express substance P and that this expression is upregulated by lipopolysacharide. Human monocytes/macrophages also express neurokinin1 receptor messenger ribonucleic acid, suggesting an autocrine effect of substance P on these cells.

Evaluating procedural skills competence: inter-rater reliability of expert and non-expert observers.

PURPOSE: To examine the inter-rater reliability of expert and non-expert observers when they used objective structured checklists to evaluate candidates' performances on three simulated medical procedures. METHOD: Simulations and structured checklists were developed for three medical procedures: endotracheal intubation, application of a forearm cast, and suturing a simple skin laceration. Groups comprised of two expert and two non-expert observers scored the performances of 101 procedures by 38 medical trainees and practitioners of varying skill levels. Inter-rater reliability was assessed using Pearson correlation coefficients. RESULTS: Inter-rater reliability was good for expert/expert, expert/non-expert, and non-expert/non-expert pairings in all three skills simulations. CONCLUSION: Both expert and non-expert observers demonstrated good inter-rater reliability when using structured checklists to assess procedural skills. Further study is required to determine whether this conclusion may be extrapolated to other study groups or procedures.

Impact of p16 expression on surgical management of malignant melanoma and pancreatic carcinoma.

BACKGROUND: Recent advances in molecular oncology have provided explanations at the DNA level for the malignant transformation and metastatic potential of various cancers. Malignant melanoma and pancreatic cancer may be classified together in both these cancers exhibit mutations in, or loss of, the cell-cycle inhibitory gene, p16. This paper reviews the current literature on p16 expression in melanoma and pancreatic cancer, explores factors that place patients with these cancers in categories of high risk for metastases or recurrence, and addresses whether aberrant gene expressions should influence awareness of and current recommendations for the management of these aggressive cancers. METHODS: A computerized literature search was performed utilizing OVID Technology's Medline database from 1993 to 1998. RESULTS: Both familial as well as sporadic cases of malignant melanoma and pancreatic carcinoma are reported in the literature. Although a low percentage of cases of either malignancy have p16 mutations, a higher risk of their development has been reported to occur in certain families with p16 germline mutations. CONCLUSIONS: The increased risk determined in these families may serve to heighten awareness of the influence of positive family history of these cancers in the evaluation of patients.

A cis repression sequence adjacent to the transcription start site of the human cytomegalovirus US3 gene is required to down regulate gene expression at early and late times after infection.

Human cytomegalovirus has two enhancer-containing immediate-early (IE) promoters with a cis repression sequence (CRS) positioned immediately upstream of the transcription start site, designated the major IE (MIE) promoter and the US3 promoter. The role of the CRS upstream of the US3 transcription start site in the context of the viral genome was determined by comparing the levels of transcription from these two enhancer-containing promoters in recombinant viruses with a wild-type or mutant CRS. Upstream of the CRS of the US3 promoter was either the endogenous enhancer (R2) or silencer (R1). The downstream US3 gene was replaced with the indicator gene chloramphenicol acetyltransferase (CAT). Infected permissive human fibroblast cells or nonpermissive, undifferentiated monocytic THP-1 cells were analyzed for expression from the US3 promoter containing either the wild-type or mutant CRS. With the wild-type CRS, the maximum level of transcription in permissive cells was detected within 4 to 6 h after infection and then declined. With the mutant CRS and the R2 enhancer upstream, expression from the US3 promoter continued to increase throughout the viral replication cycle to levels 20- to 40-fold higher than for the wild type. In nonpermissive or permissive monocytic THP-1 cells, expression from the US3 promoter was also significantly higher when the CRS was mutated. Less expression was obtained when only the R1 element was present, but expression was higher when the CRS was mutated. Thus, the CRS in the enhancer-containing US3 promoter appears to allow for a short burst of US3 gene expression followed by repression at early and late times after infection. Overexpression of US3 may be detrimental to viral replication, and its level of expression must be stringently controlled. The role of the CRS and the viral IE86 protein in controlling enhancer-containing promoters is discussed.

Was Dom Perignon really blind?

Many sources perpetuate the tripartite myth that Dom Perignon was the blind inventor of champagne, whose senses of taste and smell were enhanced by his loss of vision. This myth, however, is seemingly contradicted by historical fact. Not only do ancient references suggest that sparkling wine existed long before Perignon's time, but the making of champagne was a scientific process that required careful measuring, weighing, and record keeping, and it is unlikely that Perignon was blind when he was perfecting champagne. While the truth regarding Dom Perignon's blindness has disappeared during the more than two and a half centuries since his death, it is interesting to speculate why he may have lost vision at some stage of life. A brief history of Perignon's discovery of the secret of champagne and the blindness myth is traced, and a differential diagnosis is given, including cataracts, uncorrected refractive error, alcohol toxicity, and champagne-related ocular/cerebral trauma.