A SHORT HISTORY OF OCCUPATIONAL DISEASE: 2. ASBESTOS, CHEMICALS, RADIUM AND BEYOND.

Historically, the weighing out and manipulation of dangerous chemicals frequently occurred without adequate protection from inhalation or accidental ingestion. The use of gloves, eye protection using goggles, masks or visors was scant. From Canary Girls and chimney sweeps to miners, stone cutters and silo fillers, these are classic exemplars of the subtle (and in some cases not so subtle) effects that substances, environments and practices can have on individual health.

A SHORT HISTORY OF OCCUPATIONAL DISEASE: 1. LABORATORY-ACQUIRED INFECTIONS.

Laboratory-acquired infections are as old as laboratories themselves. As soon as the culture of microorganisms was introduced, so too was their transfer to laboratory workers. It is only in relatively recent history that such infections have been fully understood, and methods of spread and their prevention or avoidance developed. This paper endeavours to provide an overview of the history of laboratory-acquired infection and the steps taken, particularly in the UK, for its prevention.

A SHORT HISTORY OF OCCUPATIONAL DISEASE: 3. LEISURE CAN MAKE YOU SICK.

The risk of infection associated with occupations can, and does, extend to certain leisure and sports activities. Generally, such pastimes are regarded as important for human health and mental wellbeing. However, infections may, rarely, be acquired during leisure activities that include water sports and water-related relaxation, and certain sports.

The use of a negative pressure wound management system in perineal wound closure after extralevator abdominoperineal excision (ELAPE) for low rectal cancer.

BACKGROUND: Perineal wound healing is a significant challenge after extralevator abdominoperineal excision (ELAPE) due to a high rate of wound breakdown. Negative pressure therapy has proven benefits in open wounds, and recently a negative pressure system has been developed for use on closed wounds at high risk of breakdown, such as apronectomy and hysterectomy. The aim of the present study was to determine whether negative pressure therapy applied to closed perineal wounds after ELAPE improved wound healing and compare outcomes to the published literature and outcomes from a historical cohort of patients who had undergone 'standard' abdominoperineal resection (APR) and primary closure of the perineal wounds. METHODS: Prospective data on consecutive patients having ELAPE in the period from November 2012 to April 2015 were collected. The pelvic floor defect was reconstructed with biologic mesh. The adipose tissue layer was closed with vicryl sutures, a suction drain was left in the deep layer, the subcuticular layer and skin were closed, and the negative pressure system was applied. Any wound breakdown within the first 30 days postoperatively was recorded. RESULTS: Of the 32 consecutive ELAPE patients whose perineal wounds were closed within 30 days with the use of the negative pressure system, there was 1 patient with major perineal wound breakdown and 2 patients with a 1 cm superficial wound defect, which needed no further treatment. In the remaining 29 (90 %) patients, the perineal wounds healed fully without complications. Twenty-five patients underwent standard APR in 2010-2011 with primary closure of their perineal wounds. Ten out of 25(40 %) of patients who had undergone standard APR and primary closure of perineal wounds had major wound complications (p = 0.01). CONCLUSIONS: Our results suggest that after ELAPE the application of a negative pressure system to the perineal wound closed with biologic mesh may reduce perineal wound complications and may reduce the need for major perineal reconstruction.

In a 12-allele analysis HLA-DPB1 matching is associated with improved OS in leukaemic and myelodysplastic patients receiving myeloablative T-cell-depleted PBSCT from unrelated donors.

The effect on survival of including HLA-DPB1 in a 12-allele matching strategy was retrospectively evaluated in 130 patients with acute leukaemia and myelodysplasia undergoing T-cell-depleted PBSC transplantation using unrelated donors. Patients received alemtuzumab in vivo T-cell depletion as part of a myeloablative (MA; n=61) or reduced-intensity conditioning regimen (n=69). No difference in OS was seen with single-locus mismatching (mm) when 10 conventional alleles (HLA-A, B, C, DRB1 and DQB1) were considered. However, the addition of HLA-DPB1 matching data proved highly discriminatory. Mismatches were identified in 87% of patients previously considered fully matched (1DPmm=49pts: 2DPmm=28pts), and in the 9/10 group 22 patients were reclassified as double and 16 as triple mismatches. In 10/10 transplants, there was a distinct trend to poorer OS with double DPB1 mm. If all 12 loci were considered, 98% of single mm were at HLA-DPB1. Furthermore, cumulative mm at two or more loci was associated with significantly poorer 3-year OS (34% vs 48%, P=0.013: hazard ratio 1.8 (95% confidence interval 1.14-3.06; P=0.017), although his detrimental effect was only apparent using MA conditioning, in which reduced OS was associated with increased chronic GVHD (61% vs 16%, P=0.018) and nonrelapse mortality (30% vs 9%, P=0.039).

The 'Green Revolution' dwarfing genes play a role in disease resistance in Triticum aestivum and Hordeum vulgare.

The Green Revolution dwarfing genes, Rht-B1b and Rht-D1b, encode mutant forms of DELLA proteins and are present in most modern wheat varieties. DELLA proteins have been implicated in the response to biotic stress in the model plant, Arabidopsis thaliana. Using defined wheat Rht near-isogenic lines and barley Sln1 gain of function (GoF) and loss of function (LoF) lines, the role of DELLA in response to biotic stress was investigated in pathosystems representing contrasting trophic styles (biotrophic, hemibiotrophic, and necrotrophic). GoF mutant alleles in wheat and barley confer a resistance trade-off with increased susceptibility to biotrophic pathogens and increased resistance to necrotrophic pathogens whilst the converse was conferred by a LoF mutant allele. The polyploid nature of the wheat genome buffered the effect of single Rht GoF mutations relative to barley (diploid), particularly in respect of increased susceptibility to biotrophic pathogens. A role for DELLA in controlling cell death responses is proposed. Similar to Arabidopsis, a resistance trade-off to pathogens with contrasting pathogenic lifestyles has been identified in monocotyledonous cereal species. Appreciation of the pleiotropic role of DELLA in biotic stress responses in cereals has implications for plant breeding.

Randomized clinical trial of metronidazole ointment versus placebo in perianal Crohn's disease.

BACKGROUND: The potential for metronidazole 10 per cent ointment to exert therapeutic benefit in perianal Crohn's disease, while minimizing the adverse effects found with oral metronidazole, was evaluated in a randomized placebo-controlled study. METHODS: Subjects with perianal Crohn's disease were randomized to metronidazole 10 per cent ointment, 0.7 g applied perianally three times daily, or placebo ointment. The Perianal Crohn's Disease Activity Index (PCDAI) was scored at baseline and after 4 weeks of treatment. Perianal pain was assessed on a visual analogue scale. RESULTS: Seventy-four subjects (33 metronidazole, 41 placebo) were evaluated. The mean(s.e.m.) reduction in PCDAI score at 4 weeks was 2.4(0.5) in the metronidazole group and 2.2(0.4) in the placebo group (P = 0.660). More subjects in the metronidazole group than the placebo group showed a reduction in PCDAI score of at least 5 points (10 of 27 versus 4 of 34; P = 0.031). Perianal discharge was reduced significantly in metronidazole-treated subjects (P = 0.012). A greater reduction in perianal pain was seen in the metronidazole group, which approached statistical significance (P = 0.059). No serious adverse events were reported. CONCLUSION: Metronidazole 10 per cent ointment was not effective in the reduction of PDCAI score, but some secondary outcomes showed improvement suggestive of a treatment effect. It is well tolerated, with minimal adverse effects, and has potential as treatment for pain and discharge associated with perianal Crohn's disease. REGISTRATION NUMBER: NCT00509639 (http://www.clinicaltrials.gov).

Shoulder-pad sign of amyloidosis: structure of an Ig kappa III protein.

While amyloid infiltration of articular structures is rare, the 'shoulder-pad' sign resulting from periarticular soft tissue amyloid deposition is essentially pathognomonic for immunogloblin (Ig) (AL) amyloidosis. We report the characterization of an amyloid protein (GRA) which produced articular amyloid deposits and the shoulder-pad sign. Amyloid fibrils were isolated from soft tissue shoulder mass of a patient with systemic AL amyloidosis. The fibrils were solubilized in guanidine HCl and proteins separated by Sepharose chromatography. Amino acid sequence of fractionated protein was determined after tryptic digestion. Sequence analysis of the major amyloid protein yielded a kappa III Ig light chain structure. The entire variable region (VL) plus the constant region (CL) to residue 207 was identified; but lesser amounts of CL than VL were present. A number of amino acid residues previously not observed in kappa III VL proteins, plus a two amino acid insert (95A, 95B), were identified. Kappa III VL amyloid proteins are rare and may show an increased predilection for soft tissue deposition. While several unique amino acid residues that were identified in protein GRA may contribute to soft tissue amyloid deposition, no definite pattern is obvious from comparison with other reported kappa III amyloid proteins.

Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines.

Patients with glucocorticoid excess develop central obesity, yet in simple obesity, circulating glucocorticoid levels are normal. We have suggested that the increased activity and expression of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) generating active cortisol from cortisone within adipose tissue may be crucial in the pathogenesis of obesity. In this study primary cultures of human hepatocytes and adipose stromal cells (ASC) were used as in vitro models to investigate the tissue-specific regulation of 11betaHSD1 expression and activity. Treatment with tumor necrosis factor-alpha (TNFalpha) caused a dose-dependent increase in 11betaHSD1 activity in primary cultures of both sc [1743.1 +/- 1015.4% (TNFalpha, 10 ng/ml); P < 0.05 vs. control (100%)] and omental [375.8 +/- 57.0% (TNFalpha, 10 ng/ml); P < 0.01 vs. control (100%)] ASC, but had no effect on activity in human hepatocytes [90.2 +/- 2.8% (TNFalpha, 10 ng/ml); P = NS vs. control (100%)]. Insulin-like growth factor I (IGF-I) caused a dose-dependent inhibition of 11betaHSD1 activity in sc [49.7 +/- 15.0% (IGF-I, 100 ng/ml]; P < 0.05 vs. control (100%)] and omental [71.6 +/- 7.5 (IGF-I, 100 ng/ml); P < 0.01 vs. control (100%)] stromal cells, but not in human hepatocytes [101.8 +/- 15.7% (IGF-I, 100 ng/ml); P = NS vs. control (100%)]. Leptin treatment did not alter 11betaHSD1 activity in human hepatocytes, but increased activity in omental ASC [135.8 +/- 14.1% (leptin, 100 ng/ml); P = 0.08 vs. control (100%)]. Treatment with interleukin-1beta induced 11betaHSD1 activity and expression in sc and omental ASC in a time- and dose-dependent manner. 15-Deoxy-12,14-PGJ2, the putative endogenous ligand of the orphan nuclear receptor peroxisome proliferator-gamma, significantly increased 11betaHSD1 activity in omental cells [179.7 +/- 29.6% (1 microM); P < 0.05 vs. control (100%)] and sc [185.3 +/- 12.6% (1 microM); P < 0.01 vs. control (100%)] ASC, and it is possible that expression of this ligand may ensure continued cortisol generation to permit adipocyte differentiation. Protease inhibitors used in the treatment of human immunodeficiency virus infection are known to cause a lipodystrophic syndrome and central obesity, but saquinavir, indinavir, and neflinavir caused a dose-dependent inhibition of 11betaHSD1 activity in primary cultures of human omental ASC. 11betaHSD1 expression is increased in human adipose tissue by TNFalpha, interleukin-1beta, leptin, and orphan nuclear receptor peroxisome proliferator-gamma agonists, but is inhibited by IGF-I. This autocrine and/or paracrine regulation is tissue specific and explains recent clinical data and animal studies evaluating cortisol metabolism in obesity. Tissue-specific 11betaHSD1 regulation offers the potential for selective enzyme inhibition within adipose tissue as a novel therapy for visceral obesity.

Trend data on medical encounters: tracking a moving target.

The National Health Care Survey (NHCS), conducted by the National Center for Health Statistics, consists of separate data collection activities that can be used to track the number and content of health care encounters in the United States. Tracking even something as simple as the number of encounters, however, is complicated by the fact that the content of these encounters changes over time. Results from the NHCS indicate that the U.S. population has been receiving more drugs, more cardiac procedures, more ambulatory surgery, more therapies in nursing homes, and more home health care over time. Policymakers and researchers who examine health care trends should be wary about judging whether the number of length of encounters is positive or negative without also examining the content of these encounters.

Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone.

Polycystic ovarian syndrome (PCOS) is a complex disorder with multiple abnormalities, including hyperandrogenism, ovulatory dysfunction, and altered gonadotropin secretion. The majority of patients have elevated LH levels in plasma and a persistent rapid frequency of LH (GnRH) pulse secretion, the mechanisms of which are unclear. Earlier work has suggested that the sensitivity of the GnRH pulse generator to inhibition by ovarian steroids is impaired. We performed a study to determine whether antiandrogen therapy with flutamide could enhance feedback inhibition by estradiol (E2) and progesterone (P) in women with PCOS. Ten anovulatory women with PCOS and nine normal controls (days 8-10 of the cycle) were studied on three occasions. During each admission, LH and FSH were determined every 10 min and E2, P, and testosterone (T) every 2 h for 13 h. After 12 h, GnRH (25 ng/kg) was given iv. After the first admission, patients were started on flutamide (250 mg twice daily), which was continued for the entire study. The second admission occurred on days 8-10 of the next menstrual cycle for normal controls and on study day 28 for PCOS patients. Subjects were then given E2 transdermally (mean plasma E2, 106+/-18 pg/mL) and P by vaginal suppository to obtain varied plasma concentrations of P (mean P, 4.4+/-0.5 ng/mL; range, 0.6-9.0 ng/mL), and a third study was performed 7 days later. At baseline women with PCOS had higher LH pulse amplitude, response to GnRH, T, androstenedione, and insulin and lower sex hormone-binding globulin concentrations (P < 0.05). Most hormonal parameters were not altered by 4 weeks of flutamide, except T in controls and E2 and FSH in PCOS patients, which were lower. Of note, flutamide alone had no effect on LH pulse frequency or amplitude, mean plasma LH, or LH responsiveness to exogenous GnRH. After the addition of E2 and P for 7 days, both PCOS patients and normal controls had similar reductions in LH pulse frequency (4.0+/-0.7 and 5.8+/-0.7 pulses/12 h, respectively). This contrasts with our earlier results in the absence of flutamide, where a plasma P level of less than 10 ng/mL had minimal effects on LH pulse frequency in women with PCOS, but was effective in controls. These results suggest that although the elevated LH pulse frequency in PCOS may in part reflect impaired sensitivity to E2 and P, continuing actions of hyperandrogenemia are important for sustaining the abnormal hypothalamic sensitivity to feedback inhibition by ovarian steroids.

The influence of reverse-thread screw femoral fixation on laxity measurements after anterior cruciate ligament reconstruction with hamstring tendon.

In arthroscopically assisted anterior cruciate ligament reconstruction using hamstring tendon graft, the graft rotates slightly as the femoral screw is inserted. Its final position tends to be in the anterior half of the tunnel in right knees, resulting in clinical laxity. To perform identical procedures on left and right knees, a reverse-thread screw was designed for femoral fixation in right knees. We prospectively studied 80 patients undergoing right-knee anterior cruciate ligament reconstruction with hamstring tendon autograft. Thirty-six patients underwent reconstruction with a standard screw and 44 underwent reconstruction with a reverse-thread screw. The same technique, performed by the same surgeon, was used on all patients. At 12 months' follow-up, the average side-to-side differences on arthrometry testing were 2.00 mm for the standard screw group and 0.95 mm for the reverse-thread screw group using a manual maximum test, and 1.66 mm and 1.00 mm, respectively, using the 20-pound test. Both differences were statistically significant. Of the standard group, 23% had a manual maximum difference of 3 mm or more, compared with 8% of the reverse-thread group. A significant difference was found between these two groups for Lachman test (77% with grade 0 for the standard group compared with 92% for the reverse group) but pivot shift and Lysholm knee score were not significantly different. The use of a reverse-thread screw for femoral fixation in right-knee anterior cruciate ligament reconstructions in men significantly decreased laxity at 12 months after surgery compared with standard screw fixation.

A femoral component inserted without cement in total hip arthroplasty. A study of the Tri-Lock component with an average ten-year duration of follow-up.

Seventy-four total hip arthroplasties in sixty-six patients were performed, between 1983 and 1986, with use of a Tri-Lock femoral component inserted without cement. This tapered cobalt-chromium component has a fixed head and a circumferential proximal porous coating. Follow-up was conducted with use of a questionnaire, physical examination, and radiographic analysis. At the time of the latest follow-up, fifteen patients (eighteen hips) had died, three patients (four hips) had been lost to follow-up, and one patient (one hip) had refused to participate in the follow-up study; however, the status of fifteen hips at the time of death could be verified. Thus, clinical follow-up data were available for sixty-six of the original seventy-four hips. The average age at the time of the operation was sixty-two years (range, seventeen to eighty-four years), and the average interval between the operation and the latest follow-up evaluation was 10.0 years (range, 8.3 to 11.6 years). The Harris hip score was determined for forty-three hips (forty-one patients) in which the prosthesis was in situ at the time of the latest follow-up. The score was good for thirteen hips and excellent for twenty-eight, so the rate of clinical success was 95 per cent. Two patients had a fair result. One of them had persistent pain and the other had limited motion, but neither had radiographic evidence of loosening of the femoral or acetabular component. All forty-one patients were satisfied with the result. The probability (with standard error) of survival of the femoral component at ten years, with revision as the end point, was 0.95 +/- 0.03. The rate of revision of the femoral component because of aseptic loosening was one (2 per cent) of sixty-six. The overall rate of aseptic loosening of the femoral component in the hips that were followed radiographically was two (4 per cent) of forty-seven. Only one (2 per cent) of the forty-seven acetabular cups had evidence of aseptic loosening. There was no radiographic evidence of distal osteolysis around the prostheses that were well fixed. Proximal osteolysis was present in five (11 per cent) of forty-seven hips, but none of the lesions compromised the stability of the prosthesis or the bone and there were no associated fractures. At an average of ten years postoperatively, the Tri-Lock femoral component functioned well overall and patient satisfaction was high.

Effects of temperature on muscle pHi and phosphate metabolites in newts and lungless salamanders.

The effect of acute alterations in body temperature (BT) on intracellular pH (pHi) and phosphate metabolites was assessed in white skeletal muscle of intact newts and lungless red-backed salamanders using 31P-nuclear magnetic resonance spectroscopy. pHi decreased with increasing BT in the tail muscle of both newts and lungless red-backed salamanders. The change in pH with change in temperature from 10 to 30 degrees C was -0.018 U/degrees C in newts and -0.041 U/degrees C in red backs. The calculated alpha-imidazole for skeletal muscle cytosol did not change (0.56) in newts from 10 to 30 degrees C but fell from 0.69 to 0.43 in red-backed salamanders. Phosphocreatine (PCr)/Pi fell and Pi/beta-ATP rose with increasing temperature in both newts and red backs; however, the change was much greater in red backs. Providing the red backs with O2 at 30 degrees C led to higher pH and alpha-imidazole, comparable to that of newts, along with increased PCr/Pi and lower Pi/beta-ATP. Thus newts maintain white skeletal muscle cell cytosol alpha-imidazole constant with changes in BT, whereas red backs apparently do not. However, at the BT of preference, red backs and newts maintain similar muscle pHi and alpha-imidazole. The method of gas exchange appears to strongly influence the ability of an animal to maintain its acid-base status over a range of temperatures, and our results suggest that behavioral regulation of BT may involve alpha-imidazole regulation as well.

In vivo 19F NMR studies of hyperthermia: hydrophobic environments probed by halothane.

The steady-state distribution of the general anesthetic halothane in different rat tissues, including a renal adenocarcinoma with and without hyperthermia treatment, has been evaluated by in vivo 19F NMR spectroscopy. The 19F spectra of halothane (which is a hydrophobic probe) from within tissue show differences in the partitioning between normal rat tissues and adenocarcinoma. Muscle, as a control tissue, exhibits a single large resonance around 0 ppm. However, the adenocarcinoma exhibits two slow-exchanging resonances separated by 0.3 ppm with the one at the more hydrophobic chemical shift being more sensitive to hyperthermia treatment. The results from this tumor model suggest that 19F NMR spectroscopy may be useful first in detecting a change in hydrophobic environments using a lipophilic probe such as halothane, and secondly in monitoring the effects of hyperthermia, a treatment whose effectiveness may involve changes at the level of the plasma membrane. Under conditions of continuous delivery, a resonance which is not detected in the spectra of halothane in excised tissue appears 5 ppm downfield from the resonance for halothane localized in tissues. A rotating frame experiment is used to show that this resonance is derived from anesthetic absorbed on the tissue surface.

31P NMR investigation of vanadium-treated chick muscle.

The phosphorus NMR profile of normal and vanadium-treated chick muscle was obtained in vivo. The data show that the differentiation of breast and thigh muscles in terms of pH, lipid related metabolites, and bioenergetic parameters can be readily followed. Although the vanadium-treated chicks showed substantial retardation of growth, the only NMR parameter that was significantly affected by dietary vanadium was the pH of breast muscle, which was substantially more acidic in the vanadium-treated animals.

A prototype bioreductive DNA groove binding ligand.

Molecular mechanics calculations have been used to evaluate the potential bioreductive behaviour of several DNA minor groove binding ligands containing quinone/hydroquinone redox systems. The proposed structures are analogues of the Hoechst 33258 molecule with modifications of the benzimidazole rings. Binding energies of simple analogues indicate the reduced forms bind more strongly to the DNA minor groove. N-methylation of the imidazole ring(s) produces structures which can form extended quinone methides. These also show stronger binding in the reduced form and it is speculated that such structures might provide a basis for the design of groove binding ligands which will act as bioreductive alkylating agents.

ATP, ADP, and magnesium mixed solutions: in vitro 31P NMR characterization and in vivo application to lens.

The difference between the 31P NMR resonance position of the beta-peak of ADP and the gamma-peak of ATP at a fixed monovalent ion concentration level and pH is shown in vitro to depend only on free magnesium concentration. This difference can vary by more than 1 ppm depending on the pH of the solution and free magnesium concentration. Using 31P NMR and ion-selective electrodes we have constructed experimental curves to show how calibration of experimental results can be achieved. Theoretical calculations can be used to predict the functional dependence of the chemical shift difference on the above parameters. However, using the reported ion dissociation constants the fit was not exact and the discrepancy increased at higher pH values. To demonstrate that this technique can yield valid in vivo results and to analyze a previously unreported system where free magnesium levels vary, sample spectra from lenses and enucleated eyes are given. The data show a disagreement between the present methods and the more conventional ATP method. The reason for this difference is not known although some possible reasons are suggested.