HLA Matching at the Eplet Level Protects Against Chronic Lung Allograft Dysfunction.

Donor selection in lung transplantation (LTx) is historically based upon clinical urgency, ABO compatibility, and donor size. HLA matching is not routinely considered; however, the presence or later development of anti-HLA antibodies is associated with poorer outcomes, particularly chronic lung allograft dysfunction (CLAD). Using eplet mismatches, we aimed to determine whether donor/recipient HLA incompatibility was a significant predictor of CLAD. One hundred seventy-five LTx undertaken at the Alfred Hospital between 2008 and 2012 met criteria. Post-LTx monitoring was continued for at least 12 months, or until patient death. HLA typing was performed by sequence-based typing and Luminex sequence-specific oligonucleotide. Using HLAMatchmaker, eplet mismatches between each donor/recipient pairing were analyzed and correlated against incidences of CLAD. HLA-DRB1/3/4/5+DQA/B eplet mismatch was a significant predictor of CLAD (hazard ratio [HR] 3.77, 95% confidence interval [CI]: 1.71-8.29 p < 0.001). When bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) were analyzed independently, HLA-DRB1/3/4/5 + DQA/B eplet mismatch was shown to significantly predict RAS (HR 8.3, 95% CI: 2.46-27.97 p < 0.001) but not BOS (HR 1.92, 95% CI: 0.64-5.72, p = 0.237). HLA-A/B eplet mismatch was shown not to be a significant predictor when analyzed independently but did provide additional stratification of results. This study illustrates the importance of epitope immunogenicity in defining donor-recipient immune compatibility in LTx.

Risk factors associated with incident sexually transmitted infections in HIV-positive patients in the Australian HIV Observational Database: a prospective cohort study.

OBJECTIVES: We established a subcohort of HIV-positive individuals from 10 sexual health clinics within the Australian HIV Observational Database (AHOD). The aim of this study was to assess demographic and other factors that might be associated with an incident sexually transmitted infection (STI). METHODS: The cohort follow-up was from March 2010 to March 2013, and included patients screened at least once for an STI. We used survival methods to determine time to first new and confirmed incident STI infection (chlamydia, gonorrhoea, syphilis or genital warts). Factors evaluated included sex, age, mode of HIV exposure, year of AHOD enrolment, hepatitis B or C coinfection, time-updated CD4 cell count, time-updated HIV RNA viral load, and prior STI diagnosis. RESULTS: There were 110 first incident STI diagnoses observed over 1015 person-years of follow-up, a crude rate of 10.8 [95% confidence interval (CI) 9.0-13.0] per 100 person-years. Factors independently associated with increased risk of incident STI included younger age [≥ 50 vs. 30-39 years old, adjusted hazards ratio (aHR) 0.4; 95% CI 0.2-0.8; P < 0.0001]; prior STI infection (aHR 2.5; 95% CI 1.6-3.8; P < 0.001), and heterosexual vs. men who have sex with men (MSM) as the likely route of exposure (aHR 0.2; 95% CI 0.1-0.6; P < 0.001). CONCLUSIONS: In this cohort of individualsbeing treated with antiretroviral drugs, those who were MSM, who were 30-39 years old, and who had a prior history of STI, were at highest risk of a further STI diagnosis.

HIV and aging: insights from the Asia Pacific HIV Observational Database (APHOD).

OBJECTIVES: The proportion of people living with HIV/AIDS in the ageing population (>50 years old) is increasing. We aimed to explore the relationship between older age and treatment outcomes in HIV-positive persons from the Asia Pacific region. METHODS: Patients from the Australian HIV Observational Database (AHOD) and the TREAT Asia HIV Observational Database (TAHOD) were included in the analysis. We used survival methods to assess the association between older age and all-cause mortality, as well as time to treatment modification. We used regression analyses to evaluate changes in CD4 counts after combination antiretroviral therapy (cART) initiation and determined the odds of detectable viral load, up to 24 months of treatment. RESULTS: A total of 7142 patients were included in these analyses (60% in TAHOD and 40% in AHOD), of whom 25% were >50 years old. In multivariable analyses, those aged > 50 years were at least twice as likely to die as those aged 30-39 years [hazard ratio (HR) for 50-59 years: 2.27; 95% confidence interval (CI) 1.34-3.83; HR for > 60 years: 4.28; 95% CI 2.42-7.55]. The effect of older age on CD4 count changes was insignificant (p-trend=0.06). The odds of detectable viral load after cART initiation decreased with age (p-trend=< 0.0001). The effect of older age on time to first treatment modification was insignificant (p-trend=0.21). We found no statistically significant differences in outcomes between AHOD and TAHOD participants for all endpoints examined. CONCLUSIONS: The associations between older age and typical patient outcomes in HIV-positive patients from the Asia Pacific region are similar in AHOD and TAHOD. Our data indicate that 'age effects' traverse the resource-rich and resource-limited divide and that future ageing-related findings might be applicable to each setting.

Ageing and long-term CD4 cell count trends in HIV-positive patients with 5 years or more combination antiretroviral therapy experience.

OBJECTIVES: The aim of this study was to describe the long-term changes in CD4 cell counts beyond 5 years of combination antiretroviral therapy (cART). If natural ageing leads to a long-term decline in the immune system via low-grade chronic immune activation/inflammation, then one might expect to see a greater or earlier decline in CD4 counts in older HIV-positive patients with increasing duration of cART. METHODS: Retrospective and prospective data were examined from long-term virologically stable HIV-positive adults from the Australian HIV Observational Database. We estimated mean CD4 cell count changes following the completion of 5 years of cART using linear mixed models. RESULTS: A total of 37 916 CD4 measurements were observed for 892 patients over a combined total of 9753 patient-years. Older patients (> 50 years old) at cART initiation had estimated mean (95% confidence interval) changes in CD4 counts by year-5 CD4 count strata (< 500, 500-750 and > 750 cells/µL) of 14 (7 to 21), 3 (-5 to 11) and -6 (-17 to 4) cells/µL/year. Of the CD4 cell count rates of change estimated, none were indicative of long-term declines in CD4 cell counts. CONCLUSIONS: Our results suggest that duration of cART and increasing age do not result in decreasing mean changes in CD4 cell counts for long-term virologically suppressed patients, indicating that the level of immune recovery achieved during the first 5 years of treatment is sustained through long-term cART.

Nocturnal nasal congestion and nasal resistance.

OBJECTIVES: To compare total nasal resistance (TNR) in upright and supine positions in patients who did and did not complain of nocturnal (supine) nasal congestion symptoms without daytime (upright) congestion, and to determine what other conditions were associated with nocturnal nasal congestion (NNC) symptoms. STUDY DESIGN: A prospective study comparing objectively measured nasal airflow in different positions (upright and reclining) with subjective patient symptoms. METHODS: Subjects completed a questionnaire about nasal symptoms. Anterior rhinomanometry was performed with patients upright, reclined 45 degrees, and supine. TNR in subject subsets was compared using the Student t test. RESULTS: TNR did not differ between upright patients with (n = 27) and without (n = 20) NNC. Supine TNR (P < .04) and increase in TNR (P < .02) between upright and supine was greater in patients with NNC. Smokers (n = 15, 10 with NNC, 5 without) had greater TNR increases when supine versus nonsmokers (P < .02). Patients with rhinitis symptoms (n = 29, 18 with NNC, 11 without) had greater TNR increases when supine than patients without rhinitis (P < .01). Patients who both smoked and had rhinitis (n = 11, 7 with NNC, 4 without) had a greater supine TNR than patients who smoked or had rhinitis alone (P < .02). CONCLUSIONS: Some patients without daytime nasal congestion experience NNC. They have a significantly greater TNR increase when supine versus patients without NNC. Smokers and patients with rhinitis, with or without NNC, have a significantly greater TNR increase when supine versus nonsmokers or patients without rhinitis. Smoking cessation and treatment of rhinitis may improve the patients' NNC.

Prevalence of hypersensitivity to specific fungal allergens as determined by intradermal dilutional testing.

OBJECTIVE: To determine fungal allergen reactivity prevalence by intradermal dilutional testing in patients with and without chronic rhinitis or rhinosinusitis symptoms. STUDY DESIGN: Prospective comparison of fungal allergen reactivity prevalence in symptomatic and asymptomatic patients. SETTING: University medical center. METHODS: Group I (chronic rhinitis and/or rhinosinusitis symptoms) and Group II (asymptomatic) patients underwent intradermal dilutional testing with usual and fungal allergens. RESULTS: Fungal reactivity occurred in 65% (13/20) of Group I, and 13% (4/30) of Group II (P < 0.0002 by chi(2) testing). Group I was more reactive to non-fungal allergens (85% vs. 33%, p < 0.0004), and to all allergens considered together (95% vs. 40%, p < 0.0001). CONCLUSIONS: Patients with chronic rhinitis and rhinosinusitis symptoms were more reactive to fungal and nonfungal allergens. Fungal allergens were as likely as nonfungal to elicit reactivity. SIGNIFICANCE: These findings suggest a role for fungal hypersensitivity in chronic rhinitis and chronic rhinosinusitis.

Microdebrider removal of tracheal papilloma via tracheostomy in the child with an obliterated larynx.

In children, recurrent respiratory papillomatosis is the most common benign neoplasm of the airway. The disease frequently involves the larynx and may spread to extralaryngeal sites. Use of a microdebrider has been suggested as a safe and low-cost technique which reduces operating time, compared with laser removal of laryngeal lesions. We describe a technique for using a microdebrider to remove tracheal papillomas when the larynx is obliterated with the disease.

The effect of plant growth regulator treatments on the levels of ethylene emanating from excised turgid and wilted wheat leaves.

Abscisic acid (ABA) inhibits the production of ethylene induced by water stress in excised wheat leaves and counteracts the stimulatory effect of 6-benzyladenine (BA) on this process. The stimulatory effect of BA and the inhibitory effect of ABA were equally pronounced whether external or endogenous ethylene levels were determined. When leaves were sprayed or floated on solutions of BA, indole-3-acetic acid (IAA), gibberellic acid (GA3), or ABA, the relative activities of these growth regulators on stress-induced ethylene at 10(-4) mol l(-1) were BA>IAA >GA3>controls>ABA. In non-stressed leaves, however, where the levels of ethylene produced were 2-20 times smaller, the relative activities were IAA >BA>GA3>controls>ABA. The effects of BA and ABA spray treatment on water stress induced ethylene were closely similar whether the solutions were applied 2 or 18 h prior to the initiation of water stress. The relationships between the levels of endogenous growth regulators in the plant and ethylene release induced by water stress are discussed.

The effect of light and dark periods on the production of ethylene from water-stressed wheat leaves.

Light was found to inhibit substantially (i.e. up to 88%) the production of ethylene induced by water stress in excised wheat leaves and from the shoots of intact plants. The relatively small amounts of ethylene emanating fron non-stressed leaves were also inhibited by light but to a smaller degree (i.e. up to 61%). In water-stressed leaves the degree of light inhibition of ethylene production was shown to be related to the age of the leaves; the amounts of ethylene diffusing from young leaves (i.e. 6-days old) was inhibited 52% by light whereas in older leaves (i.e. 9-days old) it was inhibited by 85%. Previous studies [Wright (1979) Planta 144, 179-188 and (1980) Planta 148, 381-388] had shown that application of 6-benzyladenine (BA) to leaves a day before wilting, greatly increases the amount of ethylene diffusing from the leaves following wilting (e.g. 8-fold), and to smaller degrees do applications of indole-3-acetic acid (IAA) and gibberellic acid (GA3). On the other hand abscisic acid (ABA) treatment reduces the amount of ethylene produced. In these earlier experiments the ethylene was collected from leaves held under dark or near-dark conditions, so in the present study the activities of these growth regulators (10(-4) mol l(-1) solutions) under dark and light conditions were compared. It was found that they maintained the same relative activities on ethylene emanation (i.e. BA>IAA>GA3>water controls>ABA) under both light and dark conditions. However, because of the inhibitory effect of light, the absolute amounts of ethylene produced from all treatments were always much higher in the dark than in the light (usually about a 6-fold difference). An interesting effect of light treatment on ethylene biosynthesis was found when water-stressed leaves were kept in dark chambers for 41/2 h and then transferred to light. Quite unexpectedly, instead of the rate of ethylene production falling immediately, it continued to be produced at the dark rate (i.e. no light inhibition!) for over 2 h before the rate began to decline, and for a much longer period (i.e. in excess of 41/2 h) if the leaves had previously been sprayed with BA. Predictably, leaves placed in the light (i.e. in leaf chambers) and then transferred to darkness, immediately or very soon produced ethylene at the dark rate. One explanation of these results, which is discussed, would be that the biosynthesis of an ethylene precursor requires an obligatory dark stage. The possible implications of these studies to a survival role of ethylene in plants during periods of water stress is discussed.

The effect of 6-benzyladenine and leaf ageing treatment on the levels of stress-induced ethylene emanating from wilted wheat leaves.

Leaf ageing was initiated in wheat leaves by floating excised leaves on distilled water in darkness for up to three days. After a given period of time the leaves were blotted and wilted to a leaf water potential (ψleaf) of approximately - 12 · 10(2) k Pa and then placed in a sealed chamber so that the stress-induced ethylene could be determined. The longer the period of leaf ageing the smaller were the levels of stress-induced ethylene. Treatments which are known to delay leaf senescence, such as floating the leaves on solutions of 6-benzyladenine (BA) or in the light instead of in the dark, were found to partly restore or even enhance the stress-induced ethylene levels. For example leaves allowed to age for 1 day whilst floating on 10(-4) mol l(-1) BA solution produced up to 200% more ethylene than freshly harvested leaves when both were subjected to water stress treatment. When BA solutions were applied as foliar sprays to wheat seedlings, the day before wilting treatment, the amount of stress-induced ethylene diffusing from the freshly harvested leaves (i.e. no leaf ageing treatment) was significantly increased. This occurred when water stress was induced in the leaves by either immersing the roots of seedlings in carbowax solution or by wilting excised leaves in a stream of warm air. There was a substantial synergistic effect between BA treatment and water stress in relation to the amount of ethylene diffusing from the leaves. This effect was 7.5-fold in experiments where excised leaves were floated on 10(-4) moll(-1) BA solutions for 1 day prior to wilting and 4.7-fold for intact plants where the BA solution was applied as a foliar spray the day before water stress induction by carbowax. We can postulate from the experiments in this paper that leaf ageing (and/or the depletion of an ethylene substrate, probably a photosynthetic product or a substance derived from it) and the level of endogenous cytokinin are probably important factors which determine the amount of ethylene emanating from leaves during water stress. Moreover, the results suggest that wheat shoots may contain sub-optimal levels of cytokinins in regard to their potential ability to produce ethylene under stress.

An increase in the "inhibitor-ß" content of detached wheat leaves following a period of wilting.

Wheat seedlings were grown under a 14-hour photoperiod and the first leaves excised at the end of the eighth dark period. The effect of treatments causing wilting on the "inhibitor-ß" content of such leaves was studied.When leaves were rapidly wilted (i.e. to a 6% fresh weight loss) and extracted immediately, the amount of "inhibitor-ß" per leaf was found to be the same as in fresh turgid leaves. However, when the leaves were maintained in a wilted condition in darkness for a period of 110 minutes, there was a marked increase in "inhibitor-ß" content.The greater the degree of wilting (i.e. up to about a 9% loss in fresh weight) the greater the eventual "inhibitor-ß" content. Moreover, the increment in "inhibitor-ß" was shown to be temperature dependent.The time lapse requirement and the temperature dependency of the "inhibitor-ß" formation suggest an enzymic conversion from a precursor.If a similar phenomenon occurs during the wilting of intact plants then the increase in this growth inhibitor might play a role in some of the physiological changes which accompany water stress.

The relationship between leaf water potential ψ leaf and the levels of abscisic acid and ethylene in excised wheat leaves.

The amount of diffusible ethylene from excised wheat leaves (Triticum aestivum L. cv. Eclipse) increased when they were subjected to water stress. The quantity of ethylene produced was related to the severity of the stress, reaching a maximum at a leaf water potential ψ leaf of approximately-12 bars. Irrespective of the severity of the stress, the maximum rate of ethylene production usually occurred between 135-270 min after applying the stress and then the rate declined. Part of the decline may have been due to an oxygen deficiency in the leaf chambers. In excised water-stressed leaves there was a sigmoid relationship between increasing ethylene and abscisic acid (ABA) levels and decreasing leaf water potential values. The two curves were displaced from each other by approximately 1 bar, with ethylene evolution leading that of ABA accumulation. The maximum rate of increase in ethylene occurred between-8 and-9 bars and for ABA between-9 and-10 bars. A significant increase in the levels of these two plant growth regulators was found when the ψ leaf decreased outside the normal diurnal ψ leaf range by 1 bar for ethylene and 2 bars for ABA. Because of the sigmoid nature of the curves there was no distinct threshold ψ leaf value triggering-off an increase in ethylene or ABA, but with ABA the curve became very steep at a ψ leaf value of-9.3 bars and this could be looked upon as a kind of "threshold" value.It seems unlikely that the stress-induced ethylene evolution in excised wheat leaves stimulated the accumulation of ABA, because when the leaves were subjected to a substantial water stress (e.g. ψ leaf bars) ABA increased immediately and at a faster rate than ethylene.

Neonatal polycythemia.

Neonatal polycythemia occurs in 2 to 12 percent of all newborn infants. It may be the result of placental transfusion but may also be associated with placental insufficiency, congenital abnormalities and endocrine or metabolic disorders. Polycythemia of the newborn requires treatment because the associated blood hyperviscosity may lead to permanent neurologic impairment. Central hematocrits over 65 percent necessitate reduction transfusion using an umbilical venous or arterial catheter.

Mechanisms of sunscreen failure.

Sunscreen is used as a primary strategy to prevent sunburn and later skin cancer. However, sunscreen use has paradoxically been associated with the increasing incidence of skin cancer. One explanation for this puzzling observation is sunscreen failure (sunburn in the setting of sunscreen). Our purpose was to evaluate mechanisms of sunscreen failure in a sunscreen-using population. We carried out an epidemiologic comparison of sunburned and nonsunburned beachgoers who used sunscreen. We found that men were less likely to use sunscreen than women (chi(2) = 11.3, df = 1, P = .001), and when it was used, men were less likely to apply sunscreen to all sunlight-exposed skin (chi(2) = 18.4, df = 1, P = .0001). Swimmers who used sunscreen were significantly more likely to be sunburned compared with nonswimming sunscreen users (Fisher exact test, df = 1). Sunscreen may fail to prevent sunburn if it is washed off during swimming or if it is not applied to all exposed skin. Epidemiologic studies that link sunscreen use to skin cancer should evaluate whether sunburn occurred in this setting.

Purification and characterization of microsomal cytochrome P-450s.

1. Eight different forms of cytochrome P-450 have been purified to electrophoretic homogeneity. Electrophoretic, spectral and catalytic properties of these cytochrome P-450s are presented and comparison is made with preparations presented elsewhere in the literature. 2. The levels of these forms of cytochrome P-450 present in liver microsomes of rats treated with various compounds have now been quantified. Several forms of cytochrome P-450 are induced, in a more or less coordinate manner, while levels of other cytochrome P-450s are lowered, during administration of commonly used inducing agents. 3. The role of cytochrome P-450 purification and characterization studies in the understanding of the total field is discussed, along with directions in which future research is needed.

Purification and characterization of liver microsomal cytochromes p-450: electrophoretic, spectral, catalytic, and immunochemical properties and inducibility of eight isozymes isolated from rats treated with phenobarbital or beta-naphthoflavone.

Eight different forms of cytochrome P-450 (P-450) were purified to electrophoretic homogeneity by a common procedure from liver microsomes of rats treated with phenobarbital or beta-naphthoflavone. Antibodies were prepared to seven of these forms in rabbits. The eight P-450s were distinguished by spectral properties of the ferric, ferrous, and ferrous carbonyl forms, apparent monomeric molecular weights, peptide mapping, immunological reactivity as discerned by double-diffusion immunoprecipitin analysis and crossed immunoelectrophoresis, and catalytic activities toward the substrates acetanilide, aminopyrine, aniline, benzo[a]-pyrene, d-benzphetamine, N,N-dimethylnitrosamine, 7-ethoxycoumarin, 7-ethoxyresorufin, ethylmorphine, p-nitroanisole, testosterone, and (R)- and (S)-warfarin. Crossed sodium dodecyl sulfate-polyacrylamide gel immunoelectrophoresis was used to estimate the levels of each of the eight forms of P-450 present in the liver microsomes of untreated rats and rats treated with phenobarbital, 5,6-benzoflavone, pregnenolone-16 alpha-carbonitrile, isosafrole, or the polychlorinated biphenyl mixture Aroclor 1254. In each situation, the sum of the levels of these eight P-450s was at least as high as the spectrally determined P-450 content. The results clearly demonstrate that individual forms of P-450 can be induced by different compounds and that a single compound can lower the level of one form of P-450 while inducing one or more other forms of P-450. Catalytic activities toward each of the substrates observed with microsomal preparations are compared to rates predicted on the basis of the content of each of the eight P-450s. These studies provide a basis for further studies on the regulation of individual P-450s, the physical properties of the different P-450s, and the metabolic consequences of changes in the forms of P-450 in rat liver models.

Basal cell carcinoma arising in a cleft lip repair scar.

BACKGROUND: A case of basal cell carcinoma (BCC) developing in the repair scar of a cleft lip is presented. OBJECTIVE: Primary BCCs arising in surgical scars are very rare and no known reported cases exist of a BCC developing in a surgically repaired cleft lip scar. METHODS: A 69-year-old white man presented with a 5 mm primary BCC on his upper lip at the site of his cleft lip repair scar. The diagnosis was made by a tangential biopsy that showed an ulcerated BCC. RESULTS: Review of the medical literature indicates that a scar may be an independent risk factor for developing BCC. CONCLUSION: BCC may rarely arise in a cleft lip repair scar.