The prevalence of respiratory symptoms among mushroom workers in Ireland.

BACKGROUND: Respiratory conditions such as asthma, bronchitis, hypersensitivity pneumonitis and upper airways symptoms have been ascribed to fungal exposures. Mushroom workers may be at risk of these as a consequence. AIMS: To assess the prevalence of respiratory symptoms in mushroom workers. METHODS: A cross-sectional study assessed 4 weeks of respiratory symptoms among mushroom workers divided into four categories of exposure, using a self-administered respiratory questionnaire and spirometry. RESULTS: The population of 191 subjects was predominantly (66%) from Eastern Europe; 61% were women and 39% were under 30. It included 73 growers, 38 composters, 26 administrators and 52 packers. Among all workers, there was a high prevalence (67%) of one or more respiratory symptoms which did not appear to vary by age, gender, pack-years of smoking or duration of employment. There was a significant improvement in respiratory symptoms in workers during absence from the workplace (P < 0.001). Spirometry readings across all groups were within normal values. Symptom profiles suggest that as many as 22 workers had symptoms of airways disease; 18 (82%) of these were mushroom growers. Growers were significantly more likely to have symptoms consistent with airways disease than all other workers, odds ratio 9.2 (95% CI 3.0-28.4). CONCLUSIONS: There was a high prevalence of respiratory symptoms among mushroom workers. Mushroom growers may be at high risk of airways disease, possibly from fungal antigens or related exposures.

Smoked drug use in patients with TB is associated with higher bacterial burden.

BACKGROUND: Smoking of illicit drugs may lead to more rapid TB disease progression or late treatment presentation, yet research on this topic is scant. We examined the association between smoked drug use and bacterial burden among patients newly initiated on drug-susceptible TB (DS-TB) therapy.METHODS: Data from 303 participants initiating DS-TB treatment in the Western Cape Province, South Africa, were analyzed. Smoked drug use was defined as self-reported or biologically verified methamphetamine, methaqualone and/or cannabis use. Proportional hazard and logistic regression models (adjusted for age, sex, HIV status and tobacco use) examined associations between smoked drug use and mycobacterial time to culture positivity (TTP), acid-fast bacilli sputum smear positivity and lung cavitation.RESULTS: People who smoked drugs (PWSD) comprised 54.8% (n = 166) of the cohort. TTP was faster for PWSD (hazard ratio 1.48, 95% CI 1.10-1.97; P = 0.008). Smear positivity was higher among PWSD (OR 2.28, 95% CI 1.22-4.34; P = 0.011). Smoked drug use (OR 1.08, 95% CI 0.62-1.87; P = 0.799) was not associated with increased cavitation.CONCLUSIONS: PWSD had a higher bacterial burden at diagnosis than those who do not smoke drugs. Screening for TB among PWSD in the community may facilitate earlier linkage to TB treatment and reduce community transmission.

Gas1 Regulates Patterning of the Murine and Human Dentitions through Sonic Hedgehog.

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

The plaque removal efficacy of a novel power brush head.

OBJECTIVE: To assess the plaque removal efficacy of an oscillating/rotating power toothbrush with novel brush head (Oral-B Precision Clean) in comparison to an American Dental Association (ADA) reference manual toothbrush. METHODS: This was a replicate-use, single-brushing, two-treatment, examiner-blind, randomized, four-period (visit) study with a crossover design. At each visit, subjects disclosed their plaque with disclosing solution for one minute, and an examiner performed a baseline (pre-brushing) plaque examination (Rustogi, et al. Modification of the Navy Plaque Index). Subjects were then instructed to brush for two minutes (according to manufacturer's instructions) with their assigned power toothbrush or as they normally do with the ADA manual brush under supervision, after which they again disclosed their plaque and were given a post-brushing plaque examination. RESULTS: Both the power brush and manual brush showed statistically significant plaque reductions from baseline for the whole mouth, along the gingival margin, and on approximal surfaces. The power brush showed statistically significant advantages (p < 0.001) over the manual brush in plaque reduction for whole mouth (28.8%), gingival margin (44.3%), and approximal surfaces (20.7%). CONCLUSION: The oscillating/rotating power toothbrush with a novel brush head showed statistically significantly superior plaque reduction (whole mouth, gingival margin, and approximal surfaces) compared to a manual toothbrush.

Merkel cell carcinoma of the head and neck in the south-east of England.

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy of the skin. Its incidence is increasing with half of cases involving the head and neck. To the best of our knowledge, few large studies have been published in the UK, and to date this is the largest reported series of head and neck MCC. We retrospectively reviewed the outcomes of patients with MCC in three hospitals in the south-east of England over a 12-year period (2008-2019). Diagnosis was based on histological data following biopsy. Overall survival and disease-specific survival were calculated using Kaplan-Meier and log-rank tests. Fifty-eight patients met the inclusion criteria (24 stage I, 22 stage II, 9 stage III, and 3 unclassified). Median disease-free survival was 36 months (95% CI 0 to 77.2) and median overall survival 50 months (95% CI 29.9 to 70). Overall five-year survival was 34.4% (95% CI 17% to 52%) with two-year survival at 62% (95% CI 48% to 76%). Five-year disease-free survival was 26.7% (95% CI 17 to 52%) with two-year disease-free survival at 54% (95% CI 40% to 68%). To date, this is the largest UK based study reporting overall and disease-free survival associated with MCC of the head and neck. Half the patients presented late, and surgery was the mainstay of treatment, augmented by adjuvant radiotherapy. There is a need to better stratify patients at risk of developing metastatic disease, with the use of sentinel lymph node biopsy and positron-emission tomography-computed tomography (PET-CT), as immunotherapy and targeted agents are now available to treat advanced disease.

Respiratory measurements and airway clearance device prescription over one year in amyotrophic lateral sclerosis.

Objective: The rates of decline in respiratory measurements, including Peak Cough Flow (PCF) have not been established in Amyotrophic Lateral Sclerosis (ALS). Additionally, optimal prescription of cough adjuncts which aim to increase cough strength are unknown. The primary aim of this study was to quantify declines in respiratory function in ALS using PCF, Sniff Nasal Inspiratory Pressure (SNIP) and Slow Vital Capacity (SVC). Secondary aims were to measure respiratory morbidity, audit the characteristics of those prescribed cough adjuncts, and compare outcomes between treated and untreated cohorts. Methods: A prospective, longitudinal, observational, cohort study evaluated respiratory measures, morbidity, and physical function in ALS patients at three monthly intervals, over one year. Patient and disease characteristics of those prescribed cough adjuncts were profiled at the time of device prescription. Results: one hundred and eight participants with mean age 62.1 ± 11.5 years participated. PCF declined rapidly at a rate of 124.8L/min/year (p < 0.001). SNIP, SVC (%predicted), and ALSFRS-R also declined significantly at rates of 18.72cmH2O, 17.49%, and 9.62 units per year respectively (p < 0.001). Thirty-two (29.6%) patients reported 56 incidences of chest infection and 21 died. Patients prescribed a cough adjunct (44.4%) had significantly lower average PCF, SNIP, SVC percent predicted, and ALSFRS-R (p < 0.001). Conclusions: This study identified a rapid rate of decline in PCF, a similar decline in SNIP, and slower declines in SVC and ALSFRS-R. Cough adjunct prescription was triggered by declining respiratory measures and recommended PCF thresholds, but also by respiratory symptoms. Chest infections were common in patients regardless of cough adjunct prescription and should be closely monitored.

Hemolysis near an ultrasonically pulsating gas bubble.

A small volume of an erythrocyte suspension was subjected to the action of a manipulated gas bubble set into stable oscillation at 20 kilohertz. Release of hemoglobin occurred when the oscillation amplitude exceeded a critical threshold. Hydrodynamic stresses resulting from acoustically induced small-scale eddying motion near the bubble may be the mechanism of hemolysis.

Non-directed bronchial lavage is a safe method for sampling the respiratory tract in critically ill patient.

Ventilated patients are at risk of acquiring ventilator-associated pneumonia. Various techniques are available for diagnosing ventilator-associated pneumonia including bronchoalveolar lavage, protected specimen brush and non-directed bronchoalveolar lavage. There is a paucity of evidence regarding the safety profile of these techniques, particularly non-directed bronchoalveolar lavage. This service evaluation aimed to establish whether non-directed bronchoalveolar lavage is a safe procedure. A prospective service evaluation of non-directed bronchoalveolar lavage on our adult intensive care unit was undertaken by a senior physiotherapist trained into carrying out the procedure, measuring pre- and post-procedure vital signs including heart rate (HR), tidal volume (VT), systolic blood pressure (SBP) and pulse oximetry (SpO2). Eighty-five episodes in 41 patients were included in the evaluation. There was a statistically significant difference between pre- and immediately post-procedure recordings for all vital signs measure. HR (min-1), means (SD) 87.1 (16.4), 91.5 (16.5), 87.5 (15.9), 87.7 (15.7) respectively pre, immediately, 5 min after and 30 min after procedure (P < 0.01). SBP mmHg, means (SD) 133.9 (26.1), 142.1 (25.6), 136.9 (25.3), 134.8 (23.4) pre, immediately, 5 min and 30 min after procedure (P < 0.01). VT mL, median (range) 0.523 (0.118-1.180), 0.512 (0.131-1.05), 0.519 (0.104-0.95), 0.534 (0.110-1.080) each pre, immediately, 5 min and 30 min post procedure (P < 0.05). SpO2 %, median (range) 98 (89-100), 100 (96-100), 98 (92-100), 97 (90-100) again each pre-, immediately post, 5 and 30 min post-procedure time-points (P < 0.0001). The statistically significant difference was not detected between pre-, 5 or 30 min post-procedure time-points. None of the changes observed were clinically significant and no untoward events happened to any of the subjects included. Non-directed bronchoalveolar lavage is a safe and inexpensive procedure that can be carried out easily in an intensive care setting by a trained physiotherapist, avoiding the need for invasive bronchoscopy.

Exploring the disclosure decisions made by physiotherapists with a specific learning difficulty.

OBJECTIVES: To explore the disclosure decisions made in the workplace by physiotherapy staff with a specific learning difficulty (SpLD). DESIGN & SETTING: An exploratory qualitative design was used, which was informed by the social model of disability. The research was undertaken in North West England. It is presented according to the Consolidated Criteria for Reporting Qualitative Research. PARTICIPANTS: A purposive sample of eight physiotherapists recognised as having a SpLD were recruited. All participants had studied on one of two programmes at a university in England between 2004-2012. Their NHS workplace experience was from across the UK. DATA GENERATION: In-depth, semi-structured interviews were undertaken within the university setting or via telephone. Interviews lasted 40 to 70minutes and were digitally recorded. An interview guide was used to direct the interview. DATA ANALYSIS: Interview data were transcribed verbatim and analysed using thematic analysis. FINDINGS: Four participants were female. The mean number of years qualified as a physiotherapist was 4.5years (SD=2.27). Three themes were identified: 'Disclosing during the workplace application'; 'Positive about disabled people scheme'; 'Disclosing in the workplace'. CONCLUSIONS: Disclosure of dyslexia is a selective process and is a central dilemma in the lives of individuals who have a concealable stigmatised identity. As a consequence, physiotherapy staff with dyslexia may choose to conceal their disability and not disclose to their employer. In order for staff with dyslexia to get the support they need in the workplace, disclosure is recommended. A number of recommendations have been made to facilitate the disclosure process.

A gamma interferon-unresponsive variant of cell line 70Z/3, IFN-4, can be partially rescued by phorbol myristate acetate.

Lipopolysaccharide (LPS) and gamma interferon (IFN-gamma) induce kappa transcription in 70Z/3 cells by different mechanisms; LPS treatment induces both NF-kappa B and OTF-2 transcription factors, but IFN-gamma treatment does not. We have dissected these two activation pathways by selecting and analyzing an LPS+ IFN- variant of 70Z/3.

Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation.

The transcription factors NFAT and AP-1 have been shown to be essential for inducible interleukin-2 (IL-2) expression in activated T cells. NFAT has been previously reported to bind to two sites in the IL-2 promoter: in association with AP-1 at the distal antigen response element at -280 and at -135. On the basis of DNase I footprinting with recombinant NFAT and AP-1 proteins, gel shift assays, and transfection experiments, we have identified three additional NFAT sites in the IL-2 promoter. Strikingly, all five NFAT sites are essential for the full induction of promoter activity in response to T-cell receptor stimulation. Four of the five NFAT sites are part of composite elements able to bind AP-1 in association with NFAT. These sites display a diverse range of cooperativity and interdependency on NFAT and AP-1 proteins for binding. One of the NFAT sites directly overlaps the CD28-responsive element. We present evidence that CD28 inducibility is conferred by the AP-1 component in NFAT-AP-1 composite elements. These findings provide further insight into the mechanisms involved in the regulation of the IL-2 promoter.

Regulation and a possible stage-specific function of Oct-2 during pre-B-cell differentiation.

The Oct-2 gene appears to encode a developmental regulator of immunoglobulin gene transcription. We demonstrate that the Oct-2 gene is expressed at low levels in a variety of transformed pre-B-cell lines and is induced specifically in these cells by lipopolysaccharide signalling. This work extends an earlier observation in the pre-B-cell line 70Z/3 and therefore suggests that the inducible expression of the Oct-2 gene, like that of the kappa gene, is a characteristic feature of the pre-B stage of B-cell development. In 70Z/3 cells, the lymphokine interleukin-1 also induces the expression of the Oct-2 and kappa loci. Interestingly, expression of the Oct-2 gene is rapidly induced at the transcriptional level and may not require de novo protein synthesis. Since the changes in the activity of the Oct-2 locus completely correlate with the changes of the activity of the kappa locus, the two genes may be transcriptionally regulated by a common trans-acting factor. In 70Z/3 cells, transforming growth factor beta, an inhibitor of kappa-gene induction, blocks the upregulation of Oct-2 but not the activation of NF-kappa B. These results suggest that the combinatorial action of increased levels of Oct-2 and activated NF-kappa B may be necessary for the proper stage-specific expression of the kappa locus.

Further observations on tuberculin reactions in active tuberculosis.

One hundred patients with active tuberculosis were tested for tuberculin reactivity within 24 hours of their admission to the hospital. Commercial intermediate tuberculin, Tween stabilized intermediate tuberculin and the Tine test as well as a mumps antigen were applied simultaneously. False negative reactions were obtained in 28 per cent with Tine testing and in 21 per cent with Tween stabilized as well as plain tuberculin. These nonreactors were clinically identifiable as seriously ill with manifestations primarily attributable to protein depletion as a result of their illness. This is not specifically related to the effects of tuberculosis itself, but can be demonstrated in patients suffering the same sequelae of other debilitating illness. After two weeks of protein supplementation via a high calorie, high protein, hospital diet, skin reactivity was restored in the vast majority of these nonreactors. It is concluded that the lack of tuberculin reactivity on hospital admission probably results from impaired lymphocyte function in patients suffering serious protein depletion as a result of their illness; it is not attributable to deficiencies in the tuberculin test itself.

Cutaneous disorders and viral gene expression in HIV-1 transgenic mice.

Patients infected with HIV-1 experience several hyperproliferative skin disorders, including seborrheic dermatitis, ichthyosis, and psoriasis. Transgenic mice carrying a subgenomic HIV-1 proviral construct lacking the gag and pol genes were found to develop proliferative epidermal lesions, manifested as diffuse epidermal hyperplasia in homozygous transgenic mice and benign papillomas in heterozygous transgenic mice. Nonpapillomatous skin from both homozygotes and heterozygotes expressed viral RNA, and the viral envelope protein gp120 was localized to the suprabasal keratinocyte. Papillomas contained increased amounts of both viral mRNA and envelope glycoprotein. Exposure of transgenic mice to doses of ultraviolet B (UV-B) irradiation that induced cutaneous injury increased viral gene expression and resulted in the development of papillomas within 14-21 days. Cutaneous injury induced by phenol and liquid nitrogen had similar effects. These data support a role for HIV-1 gene products in the pathogenesis of proliferative epidermal disorders associated with HIV-1 infection. Further, they suggest that the process of wound repair increases HIV-1 gene expression in this transgenic mouse model.

A randomized trial of interferon alpha therapy for HIV type 1 infection.

The immunologic and virologic efficacy and safety of interferon a (IFN-alpha) administered in combination with zidovudine (ZDV) and zalcitabine (ddC) was evaluated in HIV-infected subjects with CD4+ cell counts between 300 and 500 cells/ml and no more than 14 weeks of prior antiretroviral therapy. A total of 256 subjects enrolled in an open-label, randomized controlled trial. Subjects were randomized equally into treatment groups. All subjects received ZDV and ddC, while half also receive IFN-alpha (3 MU subcutaneously every 24 hr). At 48 weeks the median average area under the curve minus baseline (AAUCMB) for plasma HIV-1 RNA for the two-drug group was -0.68 versus -0.75 log10 copies/ml for the IFN-alpha group (p = 0.046). Mean HIV-1 RNA changes from baseline to 48 weeks for these groups were -0.65 and -1.12 log10 copies/ml, respectively (p = 0.010). The median AAUCMB for CD4+ cell count for the two-drug group was 28 versus -1 cells/mm3 for the IFN-alpha group (p = 0.011). Neutropenia, anemia, and drug intolerance were more common in the IFN-alpha group. This study demonstrates that IFN-alpha inhibits HIV-1 replication but attenuates the CD4+ cell response to dual therapy with ZDV and ddC.

Cluster of five children with acute encephalopathy associated with cat-scratch disease in south Florida.

Between August 12 and September 27, 1994, five children in South Florida were hospitalized at a single hospital because of encephalopathy, presenting as status epilepticus, associated with cat-scratch disease (CSD). Diagnoses were confirmed by using an indirect fluorescent antibody test to detect antibody to Bartonella henselae, the causative agent of CSD. These cases represent the first cluster of CSD encephalopathy cases to be recognized in the United States. The patients lived within 7 miles of each other and all reported contact with pet or stray cats before developing regional lymphadenopathy and encephalopathy. All recovered fully. A high proportion of 124 cats from the local area were seropositive (62%) or bacteremic (22%). This study suggests that B. henselae can be associated with geographically focal clusters of CSD encephalitis and should be considered in the evaluation of children with acute encephalopathy.

In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents.

141W94 (VX-478) is a novel HIV-1 protease inhibitor with an IC50 of 0.08 microM against HIV-1 (strain IIIB) and a mean IC50 of 0.012 microM against six HIV clinical isolates. 141W94 was synergistic on the basis of isobologram analysis with each of the following reverse transcriptase inhibitors: AZT, 935U83, 524W91, 1592U89 and ddl, 141W94 was also synergistic with saquinavir and additive with either indinavir or ritonavir. Resistance to 141W94 has been reported in vitro passage experiments. The binding of 141W94 to human alpha 1-acid glycoprotein was relatively weak (Kd = 4 microM) and the off-rate for the drug is very fast (> or = 100 s-1). Only a 2-fold reduction of in vitro antiviral activity was observed in the presence of 45% human plasma. No serious drug associated adverse experiences were reported in a Phase I placebo-controlled, single-dose escalation, pharmacokinetic and safety study. The average concentration of 141W94 at 8 and 12 h after single doses of 900 and 1200 mg, respectively, was in excess of 10 times the IC50. As 141W94 is synergistic with a variety of anti-HIV-1 agents and exhibits a unique cross resistance profile compared to other protease inhibitors, 141W94 is considered a good candidate for combination therapy.

Double-blind comparison of weekend and daily regimens of oral acyclovir for suppression of recurrent genital herpes.

The potential utility of intermittent regimens of oral acyclovir for suppression of recurrent genital herpes depends on how long the suppressive effect of the drug persists during pauses in treatment. To study this question, we admitted 38 patients in a double-blind controlled trial comparing the results of daily acyclovir treatment (200 mg t.i.d.) with treatment on weekend days only (400 mg t.i.d. on Saturday and Sunday) for suppression of recurrent genital herpes. Of the 35 patients completing the study, significantly more failures occurred in the weekend group (13/17) than in the daily group (3/18, P less than 0.001). Failures on the weekend regimen were more frequent as the week progressed (P = 0.005). The findings suggest a short-term persistence of suppression by acyclovir and hence that intermittent regimens with more closely spaced periods of treatment may be more effective than the regimen we studied. Most virus isolates studied, including all of those isolated from the patients during treatment, were sensitive to acyclovir.

Sports and clean living: a useful myth?

The effects of athletics upon participants' concern for physical health and community norms were investigated through a correlational analysis of sports participation and use of mood-altering drugs among high school seniors. Five hypotheses were tested: (1) the greater the number of sports participated in, the lower the rate of illegal substance use; (2) the greater the number of sports participated in, the lower the rate of alcohol use; (3) the greater the number of sports participated in, the lower the rate of cigarette use; (4) participation in out-of-school sports is associated with a greater diminishment of illegal substance use, alcohol use, and cigarette use than is participation in university sports or intramural sports; (5) the greater the number of sports participated in, the fewer the number of problems resulting from substance use. Only hypothesis 4 regarding diminished use of cigarettes was upheld but the correlations for hypothesis 4 are small, accounting for less than 3% of the variance. It is concluded that participation in all types of sports has very little effect on the use of mood-altering drugs. Athletics as a social institution, however, can continue to symbolize goodness, fun and fair play irrespective of the private behavior of the participants.