Gingival Swelling as the Initial Manifestation of Granulomatosis with Polyangiitis

We describe a case of granulomatosis with polyangiitis (GPA; formerly named Wegener granulomatosis) that presented initially as florid areas of gingival swelling. The patient also had upper respiratory symptoms that included sinus congestion and cough of recent onset. Clinical-pathologic correlation aided the interpretation of non-specific biopsy findings and immediate referral to an appropriate medical specialist. Treatment was rendered at an early stage of disease with a good response to date. Review of the literature indicates that gingival swelling, often with the characteristic appearance of “strawberry gingivitis” may represent the initial sign of disease in 2% of patients with GPA. Biopsy of gingival lesions often shows a non-specific histologic appearance that should be interpreted in the context of the clinical appearance and pertinent medical history. The clinical investigations that lead to definitive diagnosis and treatment are presented to facilitate the management of this uncommon but potentially fatal condition.     

Debunking Lesbian Bed Death: Using Coarsened Exact Matching to Compare Sexual Practices and Satisfaction of Lesbian and Heterosexual Women

Archives of Sexual Behavior - The current study examined the prevalence and correlates of over 50 sexual practices in a national survey of heterosexual and lesbian women in relationships. Coarsened...     

Developing network adequacy standards for VA Community Care

ObjectivesTo inform how the VA should develop and implement network adequacy standards, we convened an expert panel to discuss Community Care Network (CCN) adequacy and how VA might implement network adequacy standards for community care.Data Sources/Study settingData were generated from expert panel ratings and from an audio‐recorded expert panel meeting conducted in Arlington, Virginia, in October 2017.Study DesignWe used a modified Delphi panel process involving one round of expert panel ratings provided by nine experts in network adequacy standards. Expert panel members received a list of network adequacy standard measures used in commercial and government market and were provided a rating form listing a total of 11 measures and characteristics to rate.Data Collection MethodsItems on the rating form were individually discussed during an expert panel meeting between the nine expert panel members and VA Office of Community Care leaders. Attendees addressed discordant views and generated revised or new standards accordingly. Recorded audio data were transcribed to facilitate thematic analysis regarding opportunities and challenges with implementing network adequacy standards in VA Community Care.Principal FindingsThe five highest ranked standards were network directories for Veterans, regular reporting of network adequacy data to VA, maximum wait time/distance standards, minimum ratio of providers to enrolled population, and qualitative assessments of network adequacy. During the expert panel discussion with VA Community Care leaders, opportunities and challenges implementing network adequacy standards were highlighted.ConclusionsOur expert panel shed light on priorities for network adequacy to be implemented under CCN contracts, such as developing comprehensive provider directories for Veterans to use when selecting community providers. Remaining questions focus on whether the VA could reasonably develop and implement network adequacy standards given current Congressional restraints on VA reimbursement to community providers.     

Single-cell fate mapping reveals widespread clonal ignorance of low-affinity T cells exposed to systemic infection

T cell ignorance is a specific form of immunological tolerance. It describes the maintenance of naivety in antigen-specific T cells in vivo despite the presence of their target antigen. It is thought to mainly play a role during the steady state, when self-antigens are presented in absence of costimulatory signals and at low density or to T cells of low affinity. In how far antigen-specific T cells can also remain clonally ignorant to foreign antigens, presented in the inflammatory context of systemic infection, remains unclear. Using single-cell in vivo fate mapping and high throughput flow cytometric enrichment, we find that high-affinity antigen-specific CD8⁺ T cells are efficiently recruited upon systemic infection. In contrast, most low-affinity antigen-specific T cells ignore the priming antigen and persist in the naïve state while remaining fully responsive to subsequent immunization with a high-affinity ligand. These data establish the widespread clonal ignorance of low-affinity T cells as a major factor shaping the composition of antigen-specific CD8⁺ T cell responses to systemic infection.     

Circadian rhythms of paracetamol metabolism in healthy subjects; a preliminary report

Paracetamol was used as a "probe" drug to study the circadian rhythms of metabolite ratios in man. Paracetamol was orally administered to six volunteers at different times of day, 0-8 h and 8-24 h urine samples being measured for sulphate and glucuronide formation. Results showed a wide interindividual variation in paracetamol metabolite excretion among the six subjects. However, when a 500 mg dose was administered, free paracetamol excretion was minimal when the dose was given at 12.00 h and maximal when given at 20.00 h for the 0-8 h collection period. Sulphate excretion rose slightly at night and decreased gradually during the day. Glucuronide excretion was greatest with drug administration at 16.00 h and least if paracetamol was ingested at 08.00 h. The 8-24 h profiles were roughly similar. At a higher dose (1500 mg), free paracetamol excretion showed a minimum from dosing at 20.00 h and a maximum from dosing at 24.00 h in both 0-8 h and 8-24 h collections, while the sulphate conjugate peaked for doses at 20.00 h and 8.00 h with collections at 0-8 h and 8-24 h respectively. The glucuronide conjugate was maximal for paracetamol administration at 16.00 h for both 0-8 h and 8-24 h collections. There appears to be a 12 hour phase variation in excretion; this may result from circadian rhythms in absorption and enzyme activities. These parameters may also affect metabolism at higher dose levels, so that the hepatotoxicity of paracetamol could vary with the time of dose.     

Kinds and locations of mutations arising spontaneously in the coding region of theHPRT gene of finite-life-span diploid human fibroblasts

Spontaneous thioguanine-resistant mutants were derived from populations of finite-life-span, diploid human fibroblasts by means of a fluctuation analysis. cDNA was prepared from mutantHPRT mRNA and amplified by the polymerase chain reaction, and the sequence of the product was analyzed. Exon deletions, which very likely arose from mutations in the intron splice site consensus sequences, were found in 10 of the 37 mutants examined (27% of the total). Among the 28 mutations in the coding sequence, base pair substitutions predominated (89%). With the exception of one base pair involved in a tandem mutation, all base pair substitutions resulted in alterations in the predicted amino acid sequence of the protein. In addition there were three frameshift mutations, consisting of the deletion of one or two base pairs. Although mutations occurred throughout the coding sequence, 50% (14/28) were found in the 5 portion of exon 3.     

Heterogeneity of toxicant response: sources of human variability.

While risk assessment models attempt to predict human risk to toxicant exposure, in many cases these models cannot account for the wide variety of human responses. This review addresses several primary sources of heterogeneity that may affect individual responses to drug or toxicant exposure. Consideration was given to genetic polymorphisms, age-related factors during development and senescence, gender differences associated with hormonal function, and preexisting diseases influenced by toxicant exposure. These selected examples demonstrate the need for additional steps in risk assessment that are needed to more accurately predict human responses to toxicants and drugs.