Prominent Blasts in Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder. A Reconsideration of Diagnostic Criteria.

ABSTRACT: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-LPD), recently downgraded from a T-cell lymphoma, is a poorly characterized histopathological entity. Presenting as a solitary lesion that often grows rapidly, it may raise suspicion for a cutaneous B-cell lymphoma. However, classically, the dermal lymphoid proliferation is predominantly CD4+ with a follicular T-helper profile and a smaller B-cell fraction. Diagnostic uncertainty may arise when B cells are present in large numbers, a B-cell clone is present, or large cell populations are seen. To meet the diagnostic criterion of PCSM-LPD, large cells should not constitute more than 30% of the infiltrate. The 2 cases presented in this article caused diagnostic uncertainty owing to the observation of high numbers of large cells and in one case the presence of a B-cell clone, on the background of otherwise typical clinicopathological features of PCSM-LPD. We review the literature specifically regarding the prevalence of large cell populations and their immunophenotypic characteristics and in light of this discuss whether a current diagnostic criterion should be reconsidered.

Marine mammals are natural hosts of Oceanivirga salmonicida, a bacterial pathogen of Atlantic salmon.

During 1992 and 1993, a bacterial disease occurred in a seawater Atlantic salmon Salmo salar farm, causing serious mortalities. The causative agent was subsequently named as Oceanivirga salmonicida, a member of the Leptotrichiaceae. Searches of 16S rRNA gene sequence databases have shown sequence similarities between O. salmonicida and uncultured bacterial clones from the digestive tracts of marine mammals. In the current study, oral samples were taken from stranded dolphins (common dolphin Delphinus delphis, striped dolphin Stenella coeruleoalba) and healthy harbour seals Phoca vitulina. A bacterium with growth characteristics consistent with O. salmonicida was isolated from a common dolphin. The isolate was confirmed as O. salmonicida, by comparisons to the type strain, using 16S rRNA gene, gyrB, groEL, and recA sequence analyses, average nucleotide identity analysis, and MALDI-TOF mass spectrometry. Metagenomic analysis indicated that the genus Oceanivirga represented a significant component of the oral bacterial microbiomes of the dolphins and seals. However, sequences consistent with O. salmonicida were only found in the dolphin samples. Analyses of marine mammal microbiome studies in the NCBI databases showed sequences consistent with O. salmonicida from the common dolphin, striped dolphin, bottlenose dolphin Tursiops truncatus, humpback whale Megaptera novaeangliae, and harbour seal. Sequences from marine environmental studies in the NCBI databases showed no sequences consistent with O. salmonicida. The findings suggest that several species of marine mammals are natural hosts of O. salmonicida.

Oceanivirga salmonicida gen. nov., sp. nov., a member of the Leptotrichiaceae isolated from Atlantic salmon (Salmo salar).

A pleomorphic, Gram-negative, rod-shaped, indole-, oxidase- and catalase- negative, non-spore-forming, non-motile bacterium was originally isolated in 1992 from moribund, seawater farmed Atlantic salmon with multifocal tissue necrosis. Strain AVG 2115T displayed considerable similarities with Streptobacillus moniliformis, one of the two etiological agents of rat bite fever, and has been stored as Streptobacillus sp. NCIMB 703044T. On the basis of 16S rRNA gene sequence analyses, this strain displayed >99 % sequence similarities with uncultured bacterial clones from the digestive tracts of marine mammals, followed by Sneathia sanguinegens CCUG 41628T (92.7 %), 'Sneathia amnii' Sn35 (92.5 %), Caviibacter abscessus CCUG 39713T (92.2 %), Streptobacillus ratti OGS16T (91.3 %), Streptobacillus notomytis AHL 370-1T (91.2 %), S. moniliformis DSM 12112T (91.0 %), Streptobacillus felis 131000547T (90.9 %) and Streptobacillus hongkongensis DSM 26322T (89.7 %). Sequence similarities to all other taxa were below 89 %. Phylogenetic analysis for strain NCIMB 703044T revealed highly similar results for gyrB, groEL and recA nucleotide and deduced amino acid sequence analyses independent of the employed treeing method. Average nucleotide identities (ANI) for complete genomes ranged from 66.00 % to 72.08 % between strain NCIMB 703044T and the type strains of Sebaldella termitidis, Leptotrichiabuccalis, Streptobacillus moniliformis, Sneathia sanguinegens and Caviibacter abscessus. Chemotaxonomic and physiological data of strain NCIMB 703044t were in congruence with closely related members of the family Leptotrichiaceae, represented by highly similar enzyme profiles and fatty acid patterns. MALDI-TOF MS analysis was capable to clearly discriminate strain NCIMB 703044T from all currently described taxa of the family Leptotrichiaceae. On the basis of these data we propose the novel taxon Oceanivirga salmonicida gen. nov. sp. nov. with the type strain AVG 2115T (=NCIMB 703044T) (=DSM 101867T). The G+C content is 25.4 %, genome size is 1.77 Mbp.

Contact and photocontact sensitization in chronic actinic dermatitis: a changing picture.

BACKGROUND: Patients with chronic actinic dermatitis (CAD) frequently have positive patch or photopatch tests. In our previous study (period 1987-1992), the most prominent contact allergen was the sesquiterpene lactone mix (36% of patients with CAD). OBJECTIVE: To assess whether contact allergy profiles in CAD patients between 2000 and 2005 have changed in respect to our previous data (1987-1992). PATIENTS AND METHODS: Fifty CAD patient records from 2000 to 2005 for patch and photopatch testing were retrospectively analysed and data were compared with that from 86 patients seen between 1987 and 1992. RESULTS: Thirty-two (64%) and 64 (74%) patients had positive patch or photopatch tests in 2000-2005 and 1987-1992, respectively. The allergen profile has altered. A decline in sesquiterpene lactone mix positive reactions was noted: 29 (36%) patients were positive in 1987-1992 and 10 (20%) patients in 2000-2005, but this was not significant (P = 0.08). Reactions to non-fragrance consumer allergens (i.e. p-phenylenediamine and preservatives) had risen from 7 reactions (1987-1992) to 21 reactions in 13 individuals (2000-2005) (P < 0.001). Of these allergens, p-phenylenediamine was the most common (12%; P = 0.004). CONCLUSIONS: A significant rise in positive patch tests to non-fragrance consumer allergens, particularly p-phenylenediamine, was seen in CAD patients in 2000-2005. We speculate this alteration of allergen profile may be partly due to changes in exposure patterns.

Natural Language Processing-Identified Problem Opioid Use and Its Associated Health Care Costs.

Use of prescription opioids and problems of abuse and addiction have increased over the past decade. Claims-based studies have documented substantial economic burden of opioid abuse. This study utilized electronic health record (EHR) data to identify chronic opioid therapy (COT) patients with problem opioid use (POU) and compared costs with those for COT patients without POU. This study utilized EHR and claims data from an integrated health care system. Patients received COT (≥70 days' supply in ≥1 calendar quarter, 2006-2012). Natural language processing (NLP) identified notations of opioid addiction, abuse, misuse, or overuse, and manual validation was performed. Cases had evidence of POU (index = first POU notation), and controls, sampled 9:1, did not. Health care resource utilization was measured and costs estimated using Medicare reimbursement rates. A longitudinal analysis of costs was conducted using generalized estimating equations. Adjusted analyses controlled for baseline age, gender, region, specific comorbidities, and a comorbidity index. The analysis population included 1,125 cases and 10,128 controls. Unadjusted costs were higher for cases in all three years. After controlling for covariates, total costs remained higher in cases and were significantly higher in the first year of follow-up ($38,064 vs. $31,674, P = .0048). The largest cost difference was observed in the first month of follow-up. COT patients with POU experienced significantly higher costs compared with COT patients without POU in the first year of follow-up. The greatest difference in costs was observed around identification of POU.

Randomized double-blind trial of treatment of vitiligo: efficacy of psoralen-UV-A therapy vs Narrowband-UV-B therapy.

OBJECTIVE: To compare the efficacy of oral psoralen-UV-A (PUVA) with that of narrowband-UV-B (NB-UVB) phototherapy in patients with nonsegmental vitiligo. DESIGN: Double-blind randomized study. SETTING: Phototherapy unit in a university hospital. PATIENTS: Fifty-six patients with nonsegmental vitiligo. Interventions Twice-weekly therapy with PUVA or NB-UVB. MAIN OUTCOME MEASURES: The change in body surface area affected by vitiligo and the color match of repigmented skin compared with unaffected skin were assessed after 48 sessions of therapy, at the end of the therapy course, and 12 months after the end of therapy. RESULTS: The results in the 25 patients each in the PUVA and NB-UVB groups who began therapy were analyzed. The median number of treatments was 47 in the PUVA-treated group and 97 in the NB-UVB-treated group (P = .03); we suspect this difference was because of the differences in efficacy and adverse effects between the 2 modalities, such that patients in the NB-UVB group wanted a longer course of treatment. At the end of therapy, 16 (64%) of 25 patients in the NB-UVB group showed greater than 50% improvement in body surface area affected compared with 9 (36%) of 25 patients in the PUVA group. The color match of the repigmented skin was excellent in all patients in the NB-UVB group but in only 11 (44%) of those in the PUVA group (P<.001). In patients who completed 48 sessions, the improvement in body surface area affected by vitiligo was greater with NB-UVB therapy than with PUVA therapy (P = .007). Twelve months after the cessation of therapy, the superiority of NB-UVB tended to be maintained. CONCLUSION: In the treatment of nonsegmental vitiligo, NB-UVB therapy is superior to oral PUVA therapy.

Photoadaptation during narrowband ultraviolet-B therapy is independent of skin type: a study of 352 patients.

Understanding how photoadaptation differs between individuals is important when considering susceptibility to the beneficial and harmful effects of sunlight exposure and when determining optimal phototherapy regimens. Most narrowband UVB (NB-UVB) regimens start with 70% of the minimal erythema dose (MED) with 20% increments at each treatment thereafter. We retrospectively studied 352 skin types I-IV psoriatic patients having twice weekly treatment with this regimen. Patients with high skin types tended to have high MEDs (P<0.001). By session 20 the proportion of patients who had developed erythema was approximately 60% regardless of MED. Among patients who developed erythema, the number of treatments before erythema occurred did not differ between skin types (P=0.33). We conclude that patients with high skin types photoadapt approximately equally per physical unit of UVR in comparison to those with low skin types, but they have greater photoadaptation in absolute terms because they are able to tolerate a higher initial dose of radiation. Differences in skin type or MED are not associated with clinically important differences in tendency to erythema during a standard 70/20% NB-UVB twice-weekly regimen. This regimen is suitable for all skin types I-IV patients regardless of skin type or MED.

Randomized double-blind trial of the treatment of chronic plaque psoriasis: efficacy of psoralen-UV-A therapy vs narrowband UV-B therapy.

OBJECTIVE: To compare the efficacy of oral psoralen-UV-A (PUVA) therapy with that of narrowband UV-B (NB-UVB) therapy in patients with chronic plaque psoriasis. DESIGN: Double-blind randomized study. SETTING: Phototherapy unit in a university hospital. Patients Ninety-three patients with chronic plaque psoriasis. Interventions Twice-weekly NB-UVB or PUVA therapy, starting at 70% of the minimum phototoxic or erythema dose, with 20% incremental increases. Patients were treated until clearance, up to a maximum of 30 sessions; those with clearance were followed up until relapse or for 12 months. MAIN OUTCOME MEASURES: Proportion of patients achieving clearance, number of treatments to clearance, and, among those with clearance, the proportion remaining in remission at 6 months. RESULTS: Patients with skin types V and VI had a lower rate of clearance than those with skin types I through IV (24% vs 75%; P = .001). In patients with skin types I through IV, PUVA was significantly more effective than NB-UVB at achieving clearance (84% vs 65%; P = .02). The median number of treatments to clearance was significantly lower in the PUVA group (17.0 vs 28.5; P<.001). More patients treated with PUVA vs NB-UVB were reported to have erythema at some stage during treatment (49% vs 22%; P = .004), although this difference may have been due to ascertainment bias. Six months after the cessation of therapy, 68% of PUVA-treated patients were still in remission vs 35% of NB-UVB-treated patients. Conclusion Compared with NB-UVB, PUVA achieves clearance in more patients with fewer treatment sessions and results in longer remissions.

Opioid Use in Fibromyalgia: A Cautionary Tale.

Multiple pharmacotherapies are available for the treatment of fibromyalgia (FM), including opioid analgesics. We postulate that the mechanism of action of traditional opioids predicts their lack of efficacy in FM. Literature searches of the MEDLINE and Cochrane Library databases were conducted using the search term opioid AND fibromyalgia to identify relevant articles, with no date limitations set. Citation lists in returned articles and personal archives of references were also examined for additional relevant items, and articles were selected based on the expert opinions of the authors. We found no evidence from clinical trials that opioids are effective for the treatment of FM. Observational studies have found that patients with FM receiving opioids have poorer outcomes than patients receiving nonopioids, and FM guidelines recommend against the use of opioid analgesics. Despite this, and despite the availability of alternative Food and Drug Administration-approved pharmacotherapies and the efficacy of nonpharmacologic therapies, opioids are commonly used in the treatment of FM. Factors associated with opioid use include female sex; geographic variation; psychological factors; a history of opioid use, misuse, or abuse; and patient or physician preference. The long-term use of opioid analgesics is of particular concern in the United States given the ongoing public health emergency relating to excess prescription opioid consumption. The continued use of opioids to treat FM despite a proven lack of efficacy, lack of support from treatment guidelines, and the availability of approved pharmacotherapy options provides a cautionary tale for their use in other chronic pain conditions.

The effect of solar-simulated radiation on the elicitation phase of contact hypersensitivity does not differ between controls and patients with polymorphic light eruption.

It has been suggested that polymorphic light eruption (PLE) is characterized by a failure of ultraviolet radiation (UVR)-induced immunosuppression, resulting in a type-IV hypersensitivity response to photoinduced antigens. We measured the effect of solar-simulated radiation (SSR) on the elicitation phase of contact hypersensitivity to 2,4-dinitrochlorobenzene (DNCB), in ten PLE patients and 11 controls. Subjects were given a sensitizing dose of DNCB, and 3 wk later were exposed to 0.75 and 2 minimum erythema doses (MED) of SSR on the upper inner arm. Immediately and 24 h later these sites, and a non-irradiated control site, were challenged with DNCB. The resulting increase in skin thickness was measured with high-frequency ultrasound. Overall, 2 MED caused 17%-20% suppression of elicitation responses (compared with 93% suppression of sensitization reported previously), but the effect of SSR varied greatly between subjects, with some subjects showing potentiated responses, which may be of relevance to false-positive reactions in photopatch testing. In a repeated measures general linear model, SSR overall caused significant suppression of responses (p<0.001); there was less suppression in older subjects (p=0.009) but there was no significant difference between PLE patients and age-matched normal controls. These results contrast with our previous finding of a resistance to UVR-induced suppression of sensitization to DNCB in PLE. This difference may reflect the greater importance of Langerhans cells in the sensitization phase, and is consistent with the hypothesis that PLE arises from impaired suppression of Langerhans cell activation or migration.

Using natural language processing to identify problem usage of prescription opioids.

BACKGROUND: Accurate and scalable surveillance methods are critical to understand widespread problems associated with misuse and abuse of prescription opioids and for implementing effective prevention and control measures. Traditional diagnostic coding incompletely documents problem use. Relevant information for each patient is often obscured in vast amounts of clinical text. OBJECTIVES: We developed and evaluated a method that combines natural language processing (NLP) and computer-assisted manual review of clinical notes to identify evidence of problem opioid use in electronic health records (EHRs). METHODS: We used the EHR data and text of 22,142 patients receiving chronic opioid therapy (≥70 days' supply of opioids per calendar quarter) during 2006-2012 to develop and evaluate an NLP-based surveillance method and compare it to traditional methods based on International Classification of Disease, Ninth Edition (ICD-9) codes. We developed a 1288-term dictionary for clinician mentions of opioid addiction, abuse, misuse or overuse, and an NLP system to identify these mentions in unstructured text. The system distinguished affirmative mentions from those that were negated or otherwise qualified. We applied this system to 7336,445 electronic chart notes of the 22,142 patients. Trained abstractors using a custom computer-assisted software interface manually reviewed 7751 chart notes (from 3156 patients) selected by the NLP system and classified each note as to whether or not it contained textual evidence of problem opioid use. RESULTS: Traditional diagnostic codes for problem opioid use were found for 2240 (10.1%) patients. NLP-assisted manual review identified an additional 728 (3.1%) patients with evidence of clinically diagnosed problem opioid use in clinical notes. Inter-rater reliability among pairs of abstractors reviewing notes was high, with kappa=0.86 and 97% agreement for one pair, and kappa=0.71 and 88% agreement for another pair. CONCLUSIONS: Scalable, semi-automated NLP methods can efficiently and accurately identify evidence of problem opioid use in vast amounts of EHR text. Incorporating such methods into surveillance efforts may increase prevalence estimates by as much as one-third relative to traditional methods.

Automated prediction of risk for problem opioid use in a primary care setting.

UNLABELLED: Identification of patients at increased risk for problem opioid use is recommended by chronic opioid therapy (COT) guidelines, but clinical assessment of risks often does not occur on a timely basis. This research assessed whether structured electronic health record (EHR) data could accurately predict subsequent problem opioid use. This research was conducted among 2,752 chronic noncancer pain patients initiating COT (≥70 days' supply of an opioid in a calendar quarter) during 2008 to 2010. Patients were followed through the end of 2012 or until disenrollment from the health plan, whichever was earlier. Baseline risk indicators were derived from structured EHR data for a 2-year period prior to COT initiation. Problem opioid use after COT initiation was assessed by reviewing clinician-documented problem opioid use in EHR clinical notes identified using natural language processing techniques followed by computer-assisted manual review of natural language processing-positive clinical notes. Multivariate analyses in learning and validation samples assessed prediction of subsequent problem opioid use. The area under the receiver operating characteristic curve (c-statistic) for problem opioid use was .739 (95% confidence interval = .688, .790) in the validation sample. A measure of problem opioid use derived from a simple weighted count of risk indicators was found to be comparably predictive of the natural language processing measure of problem opioid use, with 60% sensitivity and 72% specificity for a weighted count of ≥4 risk indicators. PERSPECTIVE: An automated surveillance method utilizing baseline risk indicators from structured EHR data was moderately accurate in identifying COT patients who had subsequent problem opioid use.

The prevalence of problem opioid use in patients receiving chronic opioid therapy: computer-assisted review of electronic health record clinical notes.

To estimate the prevalence of problem opioid use, we used natural language processing (NLP) techniques to identify clinical notes containing text indicating problem opioid use from over 8 million electronic health records (EHRs) of 22,142 adult patients receiving chronic opioid therapy (COT) within Group Health clinics from 2006 to 2012. Computer-assisted manual review of NLP-identified clinical notes was then used to identify patients with problem opioid use (overuse, misuse, or abuse) according to the study criteria. These methods identified 9.4% of patients receiving COT as having problem opioid use documented during the study period. An additional 4.1% of COT patients had an International Classification of Disease, version 9 (ICD-9) diagnosis without NLP-identified problem opioid use. Agreement between the NLP methods and ICD-9 coding was moderate (kappa = 0.61). Over one-third of the NLP-positive patients did not have an ICD-9 diagnostic code for opioid abuse or dependence. We used structured EHR data to identify 14 risk indicators for problem opioid use. Forty-seven percent of the COT patients had 3 or more risk indicators. The prevalence of problem opioid use was 9.6% among patients with 3 to 4 risk indicators, 26.6% among those with 5 to 6 risk indicators, and 55.04% among those with 7 or more risk indicators. Higher rates of problem opioid use were observed among young COT patients, patients who sustained opioid use for more than 4 quarters, and patients who received higher opioid doses. Methods used in this study provide a promising approach to efficiently identify clinically recognized problem opioid use documented in EHRs of large patient populations. Computer-assisted manual review of EHR clinical notes found a rate of problem opioid use of 9.4% among 22,142 COT patients over 7 years.

Ultraviolet radiation causes less immunosuppression in patients with polymorphic light eruption than in controls.

It is hypothesized that polymorphic light eruption is characterized by a partial failure of ultraviolet radiation-induced immunosuppression, resulting in a delayed-type hypersensitivity response to photo-induced antigens. We aimed to study the susceptibility of PLE patients to UVR-induced immunosuppression, by measuring the strength of sensitization to 2,4-dinitrochlorobenzene after UVR exposure, and to diphenylcyclopropenone without UVR exposure, in subjects with PLE and controls. Thirteen PLE patients and 11 controls were exposed to 1 minimum erythema dose (MED) of UVR delivered from Waldmann UV-6 bulbs to the upper inner arm. Twenty-four hours later at the same site they were exposed to a sensitizing dose of 2,4-dinitrochlorobenzene. One week later they were exposed to a sensitizing dose of diphenylcyclopropenone at a nonirradiated site. Three weeks later all subjects were challenged with four doses of 2,4-dinitrochlorobenzene and four doses of diphenylcyclopropenone. The resulting increase in skin thickness was measured with Harpenden callipers and summed over the four doses, to give a single value representing the reactivity of the subject to 2,4-dinitrochlorobenzene (Sigma DN) and diphenylcyclopropenone (Sigma DP). Among all subjects, there was a very strong correlation between Sigma DN and Sigma DP (Pearson correlation 0.56, p=0.004). The strength of the reaction to 2,4-dinitrochlorobenzene relative to the reaction to diphenylcyclopropenone was significantly greater among PLE patients than controls (p=0.04 independent samples t test of Sigma DP-Sigma DN). We conclude that induction of sensitization by 2,4-dinitrochlorobenzene is suppressed less by UVR in patients with PLE than in healthy controls.

The role of microtubules in structural remodeling and the progression to heart failure.

BACKGROUND: Ventricular remodeling is a consistent feature of the heart's response to hypertrophic stimuli and progression to failure. One cytoskeletal structure in ventricular cardiac myocytes, microtubules, make up only a small proportion of tissue protein but are an essential component for growth in cells. The response of microtubules to different hypertrophic stimuli in postmitotic adult heart has been variable. METHODS AND RESULTS: Some models of induced pressure overload hypertrophy have reported microtubule upregulation at the message and protein levels. Furthermore, this microtubule plasticity appears to be responsible for the contractile dysfunction observed in these models. However, studies on other hypertrophic models report little or no microtubule plasticity despite contractile dysfunction. New immunocytochemical, immunoblotting, and mechanical data are reported from a progressive left ventricular pressure overload model, the spontaneously hypertensive rat. CONCLUSIONS: No changes were observed in microtubule expression or in either systolic or diastolic function after the reduction or removal of microtubules with colchicine. Thus cellular mechanical dysfunction after hypertrophic stimuli may or may not be mediated microtubule remodeling depending upon the experimental model and conditions.