Beyond "purposeful and planned": varied trajectories of healthcare transition from pediatric to adult-oriented care among youth living with HIV.

Healthcare transition (HCT) from pediatric to adult-oriented healthcare is ideally conceptualized as a planned, continuous process characterized by communication between multiple stakeholders. However, empirical data is lacking regarding processes through which youth living with HIV (YLHIV) are actually transitioned to adult care. We conducted a qualitative study to gain a more comprehensive understanding of both pediatric and adult provider perspectives on the HCT process for YLHIV. Our study included focus groups discussions with 24 (11 pediatric and 13 adult) providers at a comprehensive HIV care center in the Southeastern United States. Providers described YLHIV and their HCT trajectories as diverse and complex. They described three distinct HCT trajectories: the Ideal Transition, the Abrupt Transition, and the De Facto Transition. Providers agreed that the most important determinant of successful engagement in adult-oriented care (post-HCT) appeared to be consistent prior engagement while in pediatric care (pre-HCT). In summary, risk for disengagement is not uniform among YLHIV transitioning to adult care, and HCT does not always occur in a seamless or linear fashion. Our data suggest that interventions aiming to improve HCT should be more tailored, focusing intensified efforts on those YLHIV with difficulty maintaining consistent engagement in pediatric care.

Kaposi Sarcoma Inflammatory Cytokine Syndrome (KICS): A Rare but Potentially Treatable Condition.

Kaposi sarcoma inflammatory cytokine syndrome (KICS) is a newly-described condition affecting individuals who are HIV-positive and are infected with human herpesvirus 8 (HHV-8). This is a syndrome that in some ways mimics severe sepsis with associated acute respiratory distress syndrome, possibly requiring a ventilator and vasopressor support. However, unlike severe sepsis, antibiotics provide no benefit. Management of KICS has not been fully elucidated because of its high mortality rate. However, the syndrome has been successfully treated in some cases with immunomodulatory therapy. It is crucial for oncologists to be able to recognize this syndrome and to institute the appropriate therapy. The Oncologist 2017;22:623-625.

Chemotherapy Used to Halt Lower GI Bleeding in a Rare Case of Metastatic Choriocarcinoma to the GI Tract.

Choriocarcinoma, a nonseminomatous germ cell tumor, is a rare type of testicular malignancy that tends to occur in young males. It is, however, exceedingly rare for choriocarcinoma to involve the GI tract. In this article, we present a rare case of a 31-year-old male, diagnosed with choriocarcinoma of the left testes, along with several metastases to distant sites. The patient presented with headaches and severe lower GI bleeding due to metastases to the GI tract, which was eventually controlled with systemic chemotherapy, while requiring several units of packed RBCs during his admission to the hospital. An extensive literature review found very few cases of the occurrence of GI bleeding as a consequence of choriocarcinoma due to metastases to the GI tract.

Metastatic colorectal cancer in a cirrhotic liver with synchronous hepatocellular carcinoma.

We are reporting a case of a patient with a previous history of colorectal cancer (CRC) and cirrhosis, who developed concurrent liver lesions consistent with hepatocellular carcinoma (HCC); a case which is unique due to the low incidence of multiple cancers, particularly HCC in the setting of previous advanced colorectal carcinoma along, in a cirrhotic liver. We will review the known literature on multiple cancer rates found in patients with known colorectal carcinoma. We will then outline this particular patient's presentation, followed by a discussion as to why the particular concurrent development of HCC in the setting of previous CRC is of note.

Knowledge, attitudes and practices regarding cervical cancer and screening among Haitian health care workers.

It is estimated that Haiti has the highest incidence of cervical cancer in the Western Hemisphere. There are currently no sustainable and affordable cervical cancer screening programs in Haiti. The current status of screening services and knowledge of health care professionals was assessed through a Knowledge, Attitudes, and Practices survey on cervical cancer screening and prevention. It was distributed to Project Medishare for Haiti health care workers (n = 27) in the Central Plateau. The majority (22/27) of participants stated pre-cancerous cells could be detected through screening, however, only four had ever performed a pap smear. All of the participants felt a screening program should be started in their area. Our data establishes that knowledge is fairly lacking among healthcare workers and there is an opportunity to train them in simple, cost effective "screen-and-treat" programs that could have a great impact on the overall health of the population.

Mouse Paneth cell antimicrobial function is independent of Nod2.

OBJECTIVE: Although polymorphisms of the NOD2 gene predispose to the development of ileal Crohn's disease, the precise mechanisms of this increased susceptibility remain unclear. Previous work has shown that transcript expression of the Paneth cell (PC) antimicrobial peptides (AMPs) α-defensin 4 and α-defensin-related sequence 10 are selectively decreased in Nod2(-/-) mice. However, the specific mouse background used in this previous study is unclear. In light of recent evidence suggesting that mouse strain strongly influences PC antimicrobial activity, we sought to characterise PC AMP function in commercially available Nod2(-/-) mice on a C57BL/6 (B6) background. Specifically, we hypothesised that Nod2(-/-) B6 mice would display reduced AMP expression and activity. DESIGN: Wild-type (WT) and Nod2(-/-) B6 ileal AMP expression was assessed via real-time PCR, acid urea polyacrylamide gel electrophoresis and mass spectrometry. PCs were enumerated using flow cytometry. Functionally, α-defensin bactericidal activity was evaluated using a gel-overlay antimicrobial assay. Faecal microbial composition was determined using 454-sequencing of the bacterial 16S gene in cohoused WT and Nod2(-/-) littermates. RESULTS: WT and Nod2(-/-) B6 mice displayed similar PC AMP expression patterns, equivalent α-defensin profiles, and identical antimicrobial activity against commensal and pathogenic bacterial strains. Furthermore, minimal differences in gut microbial composition were detected between the two cohoused, littermate mouse groups. CONCLUSIONS: Our data reveal that Nod2 does not directly regulate PC antimicrobial activity in B6 mice. Moreover, we demonstrate that previously reported Nod2-dependent influences on gut microbial composition may be overcome by environmental factors, such as cohousing with WT littermates.

Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation.

Crohn's disease (CD) is a chronic, immune-mediated, inflammatory disorder of the intestine that has been linked to numerous susceptibility genes, including the immunity-related GTPase (IRG) M (IRGM). IRGs comprise a family of proteins known to confer resistance to intracellular infections through various mechanisms, including regulation of phagosome processing, cell motility, and autophagy. However, despite its association with CD, the role of IRGM and other IRGs in regulating intestinal inflammation is unclear. We investigated the involvement of Irgm1, an ortholog of IRGM, in the genesis of murine intestinal inflammation. After dextran sodium sulfate exposure, Irgm1-deficient [Irgm1 knockout (KO)] mice showed increased acute inflammation in the colon and ileum, with worsened clinical responses. Marked alterations of Paneth cell location and granule morphology were present in Irgm1 KO mice, even without dextran sodium sulfate exposure, and were associated with impaired mitophagy and autophagy in Irgm1 KO intestinal cells (including Paneth cells). This was manifested by frequent tubular and swollen mitochondria and increased LC3-positive autophagic structures. Interestingly, these LC3-positive structures often contained Paneth cell granules. These results suggest that Irgm1 modulates acute inflammatory responses in the mouse intestine, putatively through the regulation of gut autophagic processes, that may be pivotal for proper Paneth cell functioning.

Chemical-genetic disruption of clathrin function spares adaptor complex 3-dependent endosome vesicle biogenesis.

A role for clathrin in AP-3-dependent vesicle biogenesis has been inferred from biochemical interactions and colocalization between this adaptor and clathrin. The functionality of these molecular associations, however, is controversial. We comprehensively explore the role of clathrin in AP-3-dependent vesicle budding, using rapid chemical-genetic perturbation of clathrin function with a clathrin light chain-FKBP chimera oligomerizable by the drug AP20187. We find that AP-3 interacts and colocalizes with endogenous and recombinant FKBP chimeric clathrin polypeptides in PC12-cell endosomes. AP-3 displays, however, a divergent behavior from AP-1, AP-2, and clathrin chains. AP-3 cofractionates with clathrin-coated vesicle fractions isolated from PC12 cells even after clathrin function is acutely inhibited by AP20187. We predicted that AP20187 would inhibit AP-3 vesicle formation from endosomes after a brefeldin A block. AP-3 vesicle formation continued, however, after brefeldin A wash-out despite impairment of clathrin function by AP20187. These findings indicate that AP-3-clathrin association is dispensable for endosomal AP-3 vesicle budding and suggest that endosomal AP-3-clathrin interactions differ from those by which AP-1 and AP-2 adaptors productively engage clathrin in vesicle biogenesis.

Mouse background strain profoundly influences Paneth cell function and intestinal microbial composition.

BACKGROUND: Increasing evidence supports the central role of Paneth cells in maintaining intestinal host-microbial homeostasis. However, the direct impact of host genotype on Paneth cell function remains unclear. Here, we characterize key differences in Paneth cell function and intestinal microbial composition in two widely utilized, genetically distinct mouse strains (C57BL/6 and 129/SvEv). In doing so, we demonstrate critical influences of host genotype on Paneth cell activity and the enteric microbiota. METHODOLOGY AND PRINCIPAL FINDINGS: Paneth cell numbers were determined by flow cytometry. Antimicrobial peptide (AMP) expression was evaluated using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), acid urea-polyacrylamide gel electrophoresis, and mass spectrometry. Effects of mouse background on microbial composition were assessed by reciprocal colonization of germ-free mice from both background strains, followed by compositional analysis of resultant gut bacterial communities using terminal restriction fragment length polymorphism analysis and 16 S qPCR. Our results revealed that 129/SvEv mice possessed fewer Paneth cells and a divergent AMP profile relative to C57BL/6 counterparts. Novel 129/SvEv á-defensin peptides were identified, including Defa2/18v, Defa11, Defa16, and Defa18. Host genotype profoundly affected the global profile of the intestinal microbiota, while both source and host factors were found to influence specific bacterial groups. Interestingly, ileal α-defensins from 129/SvEv mice displayed attenuated antimicrobial activity against pro-inflammatory E. coli strains, a bacterial species found to be expanded in these animals. CONCLUSIONS AND SIGNIFICANCE: This work establishes the important impact of host genotype on Paneth cell function and the composition of the intestinal microbiota. It further identifies specific AMP and microbial alterations in two commonly used inbred mouse strains that have varying susceptibilities to a variety of disorders, ranging from obesity to intestinal inflammation. This will be critical for future studies utilizing these murine backgrounds to study the effects of Paneth cells and the intestinal microbiota on host health and disease.