Kirill Lyapichev

Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria

Perforin-2 (MPEG1) is a pore-forming, antibacterial protein with broad-spectrum activity. Perforin-2 is expressed constitutively in phagocytes and inducibly in parenchymal, tissue-forming cells. In vitro, Perforin-2 prevents the intracellular replication and proliferation of bacterial pathogens in these cells. Perforin-2 knockout mice are unable to control the systemic dissemination of methicillin-resistant Staphylococcus aureus (MRSA) or Salmonella typhimurium and perish shortly after epicutaneous or orogastric infection respectively. In contrast, Perforin-2-sufficient littermates clear the infection. Perforin-2 is a transmembrane protein of cytosolic vesicles -derived from multiple organelles- that translocate to and fuse with bacterium containing vesicles. Subsequently, Perforin-2 polymerizes and forms large clusters of 100 Å pores in the bacterial surface with Perforin-2 cleavage products present in bacteria. Perforin-2 is also required for the bactericidal activity of reactive oxygen and nitrogen species and hydrolytic enzymes. Perforin-2 constitutes a novel and apparently essential bactericidal effector molecule of the innate immune system. DOI: http://dx.doi.org/10.7554/eLife.06508.001

Enteric pathogens deploy cell cycle inhibiting factors to block the bactericidal activity of Perforin-2

Perforin-2 (MPEG1) is an effector of the innate immune system that limits the proliferation and spread of medically relevant Gram-negative, -positive, and acid fast bacteria. We show here that a cullin-RING E3 ubiquitin ligase (CRL) complex containing cullin-1 and βTrCP monoubiquitylates Perforin-2 in response to pathogen associated molecular patterns such as LPS. Ubiquitylation triggers a rapid redistribution of Perforin-2 and is essential for its bactericidal activity. Enteric pathogens such as Yersinia pseudotuberculosis and enteropathogenic Escherichia coli disarm host cells by injecting cell cycle inhibiting factors (Cifs) into mammalian cells to deamidate the ubiquitin-like protein NEDD8. Because CRL activity is dependent upon NEDD8, Cif blocks ubiquitin dependent trafficking of Perforin-2 and thus, its bactericidal activity. Collectively, these studies further underscore the biological significance of Perforin-2 and elucidate critical molecular events that culminate in Perforin-2-dependent killing of both intracellular and extracellular, cell-adherent bacteria. DOI: http://dx.doi.org/10.7554/eLife.06505.001

Radical Prostatectomy Findings in White Hispanic/Latino Men With NCCN Very Low-risk Prostate Cancer Detected by Template Biopsy.

Radical prostatectomy (RP) outcomes have been studied in White and Black non-Hispanic men qualifying for Epstein active surveillance criteria (EASC). Herein, we first analyzed such outcomes in White Hispanic men. We studied 70 men with nonpalpable Gleason score 3+3=6 (Grade Group [GG] 1) prostate cancer (PCa) with ⩽2 positive cores on biopsy who underwent RP. In 18 men, prostate-specific antigen (PSA) density (PSAD) was >0.15 ng/mL/g. Three of these had insignificant and 15 had significant PCa. The remaining 52 men qualified for EASC. One patient had no PCa identified at RP. Nineteen (37%) had significant PCa defined by volume (n=7), grade (n=7), and volume and grade (n=5). Nine cases were 3+4=7 (GG 2) (5/9 [56%] with pattern 4 <5%), 2 were 3+5=8 (GG 4), and 1 was 4+5=9 (GG 5). Patients with significant PCa more commonly had anterior dominant disease (11/19, 58%) versus patients with insignificant cancer (7/33, 21%) (P=0.01). In 12 cases with higher grade at RP, the dominant tumor nodule was anterior in 6 (50%) and posterior in 6 (median volumes: 1.1 vs. 0.17 cm3, respectively; P=0.01). PSA correlated poorly with tumor volume (r=0.28, P=0.049). Gland weight significantly correlated with PSA (r=0.54, P<0.001). While PSAD and PSA mass density correlated with tumor volume, only PSA mass density distinguished cases with significant disease (median, 0.008 vs. 0.012 &mgr;g/g; P=0.03). In summary, a PSAD threshold of 0.15 works well in predicting significant tumor volume in Hispanic men. EASC appear to perform better in White Hispanic men than previously reported outcomes for Black non-Hispanic and worse than in White non-Hispanic men. Significant disease is often Gleason score 3+3=6 (GG 1) PCa >0.5 cm3. Significant PCa is either a larger-volume anterior disease that may be detected by multiparametric magnetic resonance imaging-targeted biopsy or anterior sampling of the prostate or higher-grade smaller-volume posterior disease that in most cases should not pose immediate harm and may be detected by repeat template biopsies.

Pseudofungi A Diagnostic Pitfall

Pseudofungi are septate hyphae-like structures very similar morphologically to true fungal elements. Histologically their presence poses a diagnostic challenge as they mimic fungal infection. Accurate identification of pseudofungi is required to avoid unnecessary treatment, and this can be accomplished by careful morphologic analysis with the use of appropriate histochemical stains. We report a patient with pseudofungi within a paratracheal lymph node, describe the morphologic findings, and discuss the differential diagnosis.

Pulse granuloma of the rectum: an unusual entity.

Sir: Pulse granuloma is an unusual, foreign body type of inflammatory reaction to the cellulose moiety of plant matter instead of the starch granules. It is more commonly noted in the oral cavity, with few cases having been reported in the lung and other unusual sites such as the nasal cavity, fallopian tube, and ovary. Here, we report a case of a human immunodeficiency virus (HIV)-positive patient with a pulse granuloma located in the rectum. The histopathological features of a vegetable granuloma are very characteristic, and are therefore helpful in making a confirmatory diagnosis, without the use of any special studies. Hence, by means of this case report, we emphasize that the complete understanding and awareness of this pathological entity is mandatory. This can help in the early recognition and treatment of these patients. Microscopic examination remains the gold standard for its diagnosis, which helps the pathologist to reach a definitive diagnosis with minimal delay, and also to avoid the use of unnecessary, time-consuming investigations. A 53-year-old HIV-positive male presented with the complaint of intermittent passage of bright red blood from the rectum, along with a burning sensation. There were no associated complaints. He was a known hypertensive, and also had hyperlipidaemia. He gave a past history of an appendectomy and incisional hernia repair many years previously. On colonoscopy performed in 2011, left-sided diverticulosis with internal haemorrhoids was identified. On examination, vital signs were within normal limits. A small verrucous lesion was seen on the posterior midline of the anus, and digital rectal examination revealed another small flat, hard lesion on the anterior distal part of the rectal wall. On anoscopy, this lesion appeared to be mostly submucosal, and showed some irregularity of the mucosa. The patient underwent excision and fulguration of these abnormal lesions. On histopathological examination of the haematoxylin and eosin-stained slides of the rectal specimen, the colonic mucosa showed granulation tissue, acute and chronic inflammation, foreign body giant cells, submucosal and intramural identifiable particles of vegetable matter, and hyaline rings consistent with rectal pulse granuloma (Figures 1 and 2). Pulse granulomas have been given different designations by various authors, including names such as giant cell hyaline angiopathy, pulse granuloma, oral vegetable granuloma, hyaline ring granuloma, foodinduced granuloma, and granuloma with giant cells and hyaline change. On review of the literature, we could find only two cases of rectal pulse granuloma, one arising from the rectum itself, and the other in a rectocutaneous fistula. PubMed was used for the literature search.

Mesenteric desmoid tumour presenting with recurrent abdominal abscess and duodenal fistula: A case report and review of literature

Highlights • Mesenteric desmoid is a rare benign tumor, usually asymptomatic, but can grow aggressively and cause complications.• Recurrent intralesional abscess formation even after drainage and medical therapy should lead to the assumption of fistulization to the adjacent bowel.• Treatment should be guided by a multidisciplinary team, and operation intervention should be performed by surgeons familiar with desmoid tumor biology.

Glioblastoma multiforme of the optic chiasm: A rare case of common pathology.

Background: Malignant optic and chiasmatic gliomas are extremely rare, and are classified pathologically as anaplastic astrocytoma or glioblastoma multiforme (GBM). Approximately 40 cases of optic GBM in adults have been reported in the literature, and only five of them were described to originate from the optic chiasm. Case Description: An 82-year-old male patient with a past medical history of diabetes mellitus type 2, melanoma, and bladder cancer presented with gradual vision loss of the left eye in a period of 1 month. After neuro-ophthalmological examination, the decision of thither magnetic resonance imaging (MRI) studies was made. It showed a contrast enhancing mass in the region of the optic chiasm. In this case, imaging study was not enough to establish an accurate diagnosis and a left pterional craniotomy for biopsy and resection of the optic chiasmal mass was performed. After histological evaluation of the mass tissue, the diagnosis of GBM was made. Taking into account the patients poor condition and unfavorable prognosis he was moved to inpatient hospice. The patient deceased within 2 months after surgery. Conclusion: Chiasmal GBM is an extremely rare condition where a biopsy is necessary for accurate diagnosis and optimal treatment. Differential diagnosis for such lesions can be very difficult and include demyelinating optic neuritis and non-demyelinating inflammatory optic neuropathy (e.g., sarcoid), vascular lesions (e.g., cavernoma), compressive lesions of the optic apparatus, metastatic malignancy, and primary tumors of the anterior optic pathway. The role of chemotherapy and radiotherapy including novel stereotaxic radiosurgery methods is still unclear and will need to be evaluated.

Pulmonary Empty Spaces: Silicone Embolism-A Decade of Increased Incidence and Its Histological Diagnosis.

Pulmonary embolism (PE) is a critical complication related to multiple disorders and different medical or cosmetic procedures. This case report presents two patients who were admitted for respiratory symptoms in the setting of previously receiving silicone injections for cosmetic purposes and were diagnosed with silicone pulmonary embolism. The relevance of including questions about all cosmetic procedures as a part of a medical history is highlighted, in particular about silicone injections. The diagnosis is confirmed by histological means. Additionally, our review showed the change of most common sites of silicone injections and a significant increase in cosmetic procedures causing silicone embolism during the past twelve years.

Heterotopic Intracranial Skin Presenting as Chronic Draining Sinus After Remote Craniotomy

BACKGROUND Craniotomies for trauma are associated with a significant risk of wound complications. We report a case in which a chronic nonhealing draining sinus was caused by an ectopic epidermal lining deep to the craniotomy bone flap, adherent to the underlying dura. CASE DESCRIPTION A 61-year-old man was examined for a 3-year-old, nonhealing scalp wound resulting after a traumatic brain injury. His initial surgery consisted of an intracranial hematoma evacuation through a temporoparietal craniotomy; this was complicated by wound dehiscence and a chronic sinus draining clear fluid that did not resolve with antimicrobial therapy. Intraoperatively, a layer of hair-bearing skin adherent to the dura was found deep to the entirety of the previous bone flap. There was no dura tear or overt cerebrospinal fluid leak. This necessitated removal of the skin over the dura as well as the overlying bone flap. The resultant defect was reconstructed with a titanium mesh and hydroxyapatite cranioplasty, with a scalp rotation flap for coverage of the cutaneous defect. Pathology confirmed skin with intact adnexal structures. CONCLUSION This case demonstrates that it is possible for hair-bearing skin to grow directly on dura, deep to an intact craniotomy bone flap. With a chronic draining sinus in the absence of computed tomography and magnetic resonance imaging findings, this should be part of the differential diagnosis.

Understanding PSA and its derivatives in prediction of tumor volume: Addressing health disparities in prostate cancer risk stratification

Objectives To address health disparities in risk stratification of U.S. Hispanic/Latino men by characterizing influences of prostate weight, body mass index, and race/ethnicity on the correlation of PSA derivatives with Gleason score 6 (Grade Group 1) tumor volume in a diverse cohort. Results Using published PSA density and PSA mass density cutoff values, men with higher body mass indices and prostate weights were less likely to have a tumor volume <0.5 cm3. Variability across race/ethnicity was found in the univariable analysis for all PSA derivatives when predicting for tumor volume. In receiver operator characteristic analysis, area under the curve values for all PSA derivatives varied across race/ethnicity with lower optimal cutoff values for Hispanic/Latino (PSA=2.79, PSA density=0.06, PSA mass=0.37, PSA mass density=0.011) and Non-Hispanic Black (PSA=3.75, PSA density=0.07, PSA mass=0.46, PSA mass density=0.008) compared to Non-Hispanic White men (PSA=4.20, PSA density=0.11 PSA mass=0.53, PSA mass density=0.014). Materials and Methods We retrospectively analyzed 589 patients with low-risk prostate cancer at radical prostatectomy. Pre-operative PSA, patient height, body weight, and prostate weight were used to calculate all PSA derivatives. Receiver operating characteristic curves were constructed for each PSA derivative per racial/ethnic group to establish optimal cutoff values predicting for tumor volume ≥0.5 cm3. Conclusions Increasing prostate weight and body mass index negatively influence PSA derivatives for predicting tumor volume. PSA derivatives’ ability to predict tumor volume varies significantly across race/ethnicity. Hispanic/Latino and Non-Hispanic Black men have lower optimal cutoff values for all PSA derivatives, which may impact risk assessment for prostate cancer.