Club Cell Protein, CC10, Attenuates Acute Respiratory Distress Syndrome Induced by Smoke Inhalation.

OBJECTIVES: To evaluate the dose effects of Recombinant human Club cell 10-kDa protein (rhCC10) on lung function in a well-characterized ovine model of acute respiratory distress syndrome (ARDS) induced by smoke inhalation injury (SII); specifically, the potential of rhCC10 protein to control the inflammatory response and protect pulmonary tissue and function following SII. DESIGN: Randomized, controlled, prospective, and large animal translational studies. SETTING: University large animal intensive care unit. SUBJECTS: Thirty-six adult female sheep were surgically prepared and allocated into five groups (Sham (no SII), n = 6; 1 mg/kg/d CC10, n = 8; 3 mg/kg/d CC10, n = 7; 10 mg/kg/d CC10, n = 8; Control SII, n = 7). INTERVENTIONS: All groups except the sham group were subjected to SII with cooled cotton smoke. Then, the animals were placed on a ventilator, treated with 1, 3, and 10 mg/kg/d of intravenous rhCC10 or vehicle, divided evenly into two administrations per day every 12 h, fluid resuscitated, and monitored for 48 h in a conscious state. MEASUREMENTS AND MAIN RESULTS: The group treated with 10 mg/kg/d rhCC10 attenuated changes in the following variables: PaO2/FiO2 ratio, oxygenation index, and peak inspiratory pressure; neutrophil content in the airway and myeloperoxidase levels; obstruction of the large and small airways; systemic leakage of fluid and proteins, and pulmonary edema. CONCLUSIONS: In this study, high-dose rhCC10 significantly attenuated ARDS progression and lung dysfunction and significantly reduced systemic extravasation of fluid and proteins, normalizing fluid balance. Based on these results, rhCC10 may be considered a novel therapeutic option for the treatment of SII-induced ARDS.

Surgical anatomy of the ovine sural nerve for facial nerve regeneration and reconstruction research.

The lack of a clinically relevant animal models for research in facial nerve reconstruction is challenging. In this study, we investigated the surgical anatomy of the ovine sural nerve as a potential candidate for facial nerve reconstruction, and performed its histological quantitative analysis in comparison to the buccal branch (BB) of the facial nerve using cadaver and anesthetized sheep. The ovine sural nerve descended to the lower leg along the short saphenous vein. The length of the sural nerve was 14.3 ± 0.5 cm. The distance from the posterior edge of the lateral malleolus to the sural nerve was 7.8 ± 1.8 mm. The mean number of myelinated fibers in the sural nerve was significantly lower than that of the BB (2,311 ± 381vs. 5,022 ± 433, respectively. p = 0.003). The number of fascicles in the sural nerve was also significantly lower than in the BB (10.5 ± 1.7 vs. 21.3 ± 2.7, respectively. p = 0.007). The sural nerve was grafted to the BB with end-to-end neurorrhaphy under surgical microscopy in cadaver sheep. The surgical anatomy and the number of fascicles of the ovine sural nerve were similar of those reported in humans. The results suggest that the sural nerve can be successfully used for facial nerve reconstruction research in a clinically relevant ovine model.

Diffuse Chorangiomatosis as a Cause of Cardiomegaly, Microangiopathic Hemolytic Anemia and Thrombocytopenia in a Newborn.

INTRODUCTION: The hallmark of diffuse chorangiomatosis is capillary dysvasculogenesis, diffusely involving the placenta. It can cause massive placental enlargement and may have adverse fetal effects. CASE REPORT: A 32 weeks gestation male infant was born via cesarean section and had a placenta weighing 900 g. There was diffuse vascular proliferation involving the stem villi and intermediate villi. Short Nucleotide Polymorphism (SNP) microarray analysis of the placenta showed no biparental mosaicism or loss of heterozygosity, ruling out placental mesenchymal dysplasia. The infant also had cardiomegaly, microangiopathic hemolytic anemia and thrombocytopenia which spontaneously improved over time. CONCLUSION: Diffuse chorangiomatosis can be associated with hemolysis, thrombocytopenia and cardiomegaly in the newborn. However, once delivered, these findings can spontaneously resolve over time.

Outcomes of Congenital Zika Disease Depend on Timing of Infection and Maternal-Fetal Interferon Action.

Zika virus (ZIKV) infection during pregnancy in humans results in intrauterine growth restriction, spontaneous abortion, and microcephaly. Here, we found that fetus-derived type I interferon (IFN-I) signaling can enhance anti-ZIKV responses and provide clinical benefits to the fetus. Because IFN-λ shares signaling cascades and antiviral functions with IFN-I, we investigated the in vivo effects of IFN-λ in ZIKV-infected pregnant mice. IFN-λ administration during mid-pregnancy reduced ZIKV burden in maternal and fetal organs and alleviated placental injuries and fetal demise. In addition, prophylactic and therapeutic treatment of IFN-λ1 in a human trophoblast line, as well as in primary human amniotic epithelial cells, greatly reduced the ZIKV burden. Our data highlight IFN-λ1 as a potential therapeutic useful for women at risk for congenital Zika disease.

Xanthine oxidase contributes to sustained airway epithelial oxidative stress after scald burn.

Respiratory tract infections and pneumonia are major causes of morbidity and mortality in burn victims, however, limited studies have examined the effects of burn injury on airway epithelium. The current study examines the effect of scald burn injury on rat tracheal epithelium at 5 days after injury and tests the hypothesis that treatment with febuxostat (FBX), an inhibitor of xanthine oxidase (XO), can be protective of cell homeostasis. Sprague Dawley rats were randomly divided into uninjured (sham), injured (control) and injured and FBX treated groups, n = 8. Control and FBX treated groups received 60% total body surface area scald burn injury. The FBX group received an i. p. dose (1 mg/kg) at 1 hour after injury and every 24 hours. At 5 days after injury, the animals were sacrificed and tracheal epithelial cell lysates were collected. Malondialdehyde (MDA), ATP, and XO activity were measured. Formation of 8-OHdG in tracheal epithelium was determined using immunohistochemistry (IHC) and immunoreactivity was quantitated. MDA levels were significantly increased in injured control animals (24.8 ± 2.3) compared to sham (7.93 ± 1.2, p = 0.002). FBX treatment attenuated this response (12.6 ± 2.7, p = 0.02). ATP levels were significantly decreased in control (0.7 ± 0.16) compared to sham, (2 ± 0.14, p = 0.01). ATP levels were increased with FBX treatment (1.8 ± 0.1, p = 0.03) compared to controls. There was a significant increase in XO activity in control animals, 1.04 ± 0.06 compared to sham (0.34 ± 0.05, p = 0.03), and this response decreased with FBX treatment 0.46 ± 0.07 (p = 0.04). Immunolabeling of 8-OHdG in control animals was significantly increased (25.1 ± 0.7 compared to the sham group 5.5 ± 1.9 (p = 0.01)), and was decreased with FBX treatment (7.0 ± 2.3 compared to control (p = 0.03)). The current study indicates that lipid peroxidation and ATP depletion persist in tracheal epithelium for 5 days after injury along with increased XO activity and 8-OHdG. These effects were significantly attenuated by FBX treatment, suggesting that reactive oxygen species generated by XO contribute to airway epithelial injury following scald burn.

Herpesviradae infections in severely burned children.

OBJECTIVE: Burn-related immunosuppression can promote human herpesviridae infections. However, the effect of these infections on morbidity and mortality after pediatric burn injuries is unclear. METHODS: We retrospectively analyzed pediatric patients with burns ≥10% of the total body surface area (TBSA) who were admitted between 2010 and 2015. On clinical suspicion of a viral infection, antiviral therapy was initiated. Viral infection was confirmed via Tzanck smear, viral culture, and/or PCR. Study endpoints were mortality, days of antiviral agent administration, type of viral test used, type of viral infection, and length of hospitalization. RESULTS: Of the 613 patients were analyzed, 28 presented with clinically diagnosed viral infections. The use of Tzanck smears decreased over the past 5 years, whereas PCR and viral cultures have become standard. Patients with viral infections had significantly larger burns (53±15% vs. 38±18%, p<0.001); however, length of stay per TBSA burn was comparable (0.5±0.4 vs. 0.6±0.2, p=0.211). The most commonly detected herpesviridae was herpes simplex virus 1. Two patients died due to sepsis, which was accompanied by HSV infection. The mortality rate among all patients (2.7%) was comparable to that in the infected group (7.1%, p=0.898). Acyclovir was given systemically for 9±8days (N=76) and/or topically for 9±9days for HSV (N=39, combination of both N=33). Ganciclovir was prescribed in three cases for CMV. CONCLUSIONS: Viral infections occur more commonly in patients suffering from larger burns, and HSV infections can contribute to mortality.

Dendritic cells modulate burn wound healing by enhancing early proliferation.

Adequate wound healing is vital for burn patients to reduce the risk of infections and prolonged hospitalization. Dendritic cells (DCs) are antigen presenting cells that release cytokines and are central for the activation of innate and acquired immune responses. Studies have showed their presence in human burn wounds; however, their role in burn wound healing remains to be determined. This study investigated the role of DCs in modulating healing responses within the burn wound. A murine model of full-thickness contact burns was used to study wound healing in the absence of DCs (CD11c promoter-driven diphtheria toxin receptor transgenic mice) and in a DC-rich environment (using fms-like tyrosine kinase-3 ligand, FL- a DC growth factor). Wound closure was significantly delayed in DC-deficient mice and was associated with significant suppression of early cellular proliferation, granulation tissue formation, wound levels of TGFß1 and formation of CD31+ vessels in healing wounds. In contrast, DC enhancement significantly accelerated early wound closure, associated with increased and accelerated cellular proliferation, granulation tissue formation, and increased TGFß1 levels and CD31+ vessels in healing wounds. We conclude that DCs play an important role in the acceleration of early wound healing events, likely by secreting factors that trigger the proliferation of cells that mediate wound healing. Therefore, pharmacological enhancement of DCs may provide a therapeutic intervention to facilitate healing of burn wounds.

Nebulized Epinephrine Limits Pulmonary Vascular Hyperpermeability to Water and Protein in Ovine With Burn and Smoke Inhalation Injury.

OBJECTIVES: To test the hypothesis that nebulized epinephrine ameliorates pulmonary dysfunction by dual action-bronchodilation (ß2-adrenergic receptor agonism) and attenuation of airway hyperemia (α1-adrenergic receptor agonism) with minimal systemic effects. DESIGN: Randomized, controlled, prospective, and large animal translational studies. SETTING: University large animal ICU. SUBJECTS: Twelve chronically instrumented sheep. INTERVENTIONS: The animals were exposed to 40% total body surface area third degree skin flame burn and 48 breaths of cooled cotton smoke inhalation under deep anesthesia and analgesia. The animals were then placed on a mechanical ventilator, fluid resuscitated, and monitored for 48 hours in a conscious state. After the injury, sheep were randomized into two groups: 1) epinephrine, nebulized with 4 mg of epinephrine every 4 hours starting 1 hour post injury, n = 6; or 2) saline, nebulized with saline in the same manner, n = 6. MEASUREMENTS AND MAIN RESULTS: Treatment with epinephrine had a significant reduction of the pulmonary transvascular fluid flux to water (p < 0.001) and protein (p < 0.05) when compared with saline treatment from 12 to 48 hours and 36 to 48 hours, respectively. Treatment with epinephrine also reduced the systemic accumulation of body fluids (p < 0.001) with a mean of 1,410 ± 560 mL at 48 hours compared with 3,284 ± 422 mL of the saline group. Hemoglobin levels were comparable between the groups. Changes in respiratory system dynamic compliance, mean airway pressure, PaO2/FiO2 ratio, and oxygenation index were also attenuated with epinephrine treatment. No considerable systemic effects were observed with epinephrine treatment. CONCLUSIONS: Nebulized epinephrine should be considered for use in future clinical studies of patients with burns and smoke inhalation injury.

Browning of Subcutaneous White Adipose Tissue in Humans after Severe Adrenergic Stress.

Since the presence of brown adipose tissue (BAT) was confirmed in adult humans, BAT has become a therapeutic target for obesity and insulin resistance. We examined whether human subcutaneous white adipose tissue (sWAT) can adopt a BAT-like phenotype using a clinical model of prolonged and severe adrenergic stress. sWAT samples were collected from severely burned and healthy individuals. A subset of burn victims were prospectively followed during their acute hospitalization. Browning of sWAT was determined by the presence of multilocular adipocytes, uncoupling protein 1 (UCP1), and increased mitochondrial density and respiratory capacity. Multilocular UCP1-positive adipocytes were found in sWAT samples from burn patients. UCP1 mRNA, mitochondrial density, and leak respiratory capacity in sWAT increased after burn trauma. Our data demonstrate that human sWAT can transform from an energy-storing to an energy-dissipating tissue, which opens new research avenues in our quest to prevent and treat obesity and its metabolic complications.

Non-fecalith-induced appendicitis: etiology, imaging, and pathology.

This study aims to document the imaging and pathology findings in non-fecalith-induced appendicitis. We reviewed the imaging and pathologic findings in 40 patients with histologically proven purulent appendicitis seen over a 2-year period. Findings documented were (1) total appendiceal involvement, (2) predominant appendiceal tip involvement, (3) presence of a fecalith, and (4) presence of lymphoid hyperplasia. There were a total of 40 patients, 28 males and 12 females. The age range was 2-18 years with a mean of 11.5 years. Twenty-two (55 %) patients demonstrated classic purulent appendicitis of the whole appendix, 20 (91 %) of these appendices had a fecalith. Eighteen (45 %) patients demonstrated purulent appendicitis confined to or predominately involving the tip of the appendix, and all 18 (100 %) patients demonstrated marked lymphoid hyperplasia. Only two (11 %) of these appendices had a fecalith. Overall, a fecalith was found in only 55 % of our cases, while 45 % demonstrated no fecalith, but rather marked lymphoid hyperplasia. Lymphoid hyperplasia appeared to be the underlying predisposing cause of purulent appendicitis in these cases.

Chemokine CXCL1-Mediated Neutrophil Trafficking in the Lung: Role of CXCR2 Activation.

The chemokine CXCL1 and its receptor CXCR2 play a crucial role in host immune response by recruiting and activating neutrophils for microbial killing at the tissue site. Dysregulation in this process has been implicated in collateral tissue damage causing disease. CXCL1 reversibly exists as monomers and dimers, and it has been proposed that distinct monomer and dimer activities and the monomer-dimer equilibrium regulate the neutrophil function. However, the molecular mechanisms linking the CXCL1/CXCR2 axis and the neutrophil 'beneficial' and 'destructive' phenotypes are not known. In this study, we characterized neutrophil trafficking and its consequence in the mouse lung by the CXCL1 wild type (WT), which exists as monomers and dimers, and by a nondissociating dimer. Whereas the WT, compared to the dimer, was more active at low doses, both the WT and the dimer elicited a large neutrophil efflux at high doses. Importantly, robust neutrophil recruitment elicited by the WT or dimer was not detrimental to lung tissue integrity and, further, could not be correlated to surface CXCR2 levels. We conclude that the CXCL1 monomer-dimer distribution and receptor interactions are highly coupled and regulate neutrophil trafficking and that injury in the context of disease is a consequence of inappropriate CXCR2 activation at the target tissue and not due to mechanical forces exerted by neutrophils during recruitment.

Physiologic and molecular changes in the tracheal epithelium of rats following burn injury.

Pneumonia is the leading complication in the critical care of burn victims. Airway epithelial dysfunction compromises host defense against pneumonia. The aim of this study is to test the hypothesis that burn injury alters the physiology of the airway epithelium. A rat model of 60% TBSA third degree scald burn was used. At 24 hours after injury, tracheal epithelial ultrastructure was studied using transmission electron microscopy (TEM) and proliferation was measured by Ki67 immunohistochemistry. Mucociliary clearance (MCC) was measured using fluorescent microspheres. The level of malondialdehyde (MDA), an indicator of lipid peroxidation, was also measured. Changes in epithelial mRNA expression were measured using microarray. Burn injury led to a ten-fold reduction in MCC that was statistically significant (p = 0.007) 24 hours after injury. No significant change was noted in the morphology of tracheal epithelial cells between groups, although a marginal increase in extracellular space was noted in injured animals. Ki67 nuclear expression was significantly reduced (25%, p = 0.008) in injured rats. There was a significant increase in MDA levels in the epithelial lysate of burned animals, p = 0.001. Microarray analysis identified 59 genes with significant differences between sham and injured animals. Burn injury altered multiple important functions in rat tracheal epithelium. The decrease in MCC and cell proliferation may be due to oxidative injury. Mechanistic studies to identify physiological processes associated with changes in airway function may help in designing therapeutic agents to reduce burn-induced airway pathogenesis.

Integrity of airway epithelium in pediatric burn autopsies: Association with age and extent of burn injury.

UNLABELLED: This study examines the structural integrity of the airway epithelium in autopsy tissues from pediatric burn subjects. METHODS: A semi-quantitative score for the degree of airway epithelial integrity was made for seventy- two pediatric burn autopsies. Multivariate ordinal logistic regression was performed to identify relationships between epithelial integrity and conditions related to tissue fixation, time of death after injury, age, total body surface area burn (TBSA), extent of 3rd degree burn, presence of inhalation injury, ventilator days and pneumonia. RESULTS: No significant difference in epithelial integrity scores was identified between burn only cases and those with inhalation injury. Significant correlations with bronchiolar epithelial integrity scores were identified for age, p=0.02, and percent 3rd degree burn, p=0.02. There was no significant relationship between epithelial integrity and time between death and autopsy, p>0.44. CONCLUSIONS: Airway epithelial loss seen in autopsy tissue is not simply an artifact of tissue fixation. The degree of compromise correlates most strongly with age and degree of burn. Further studies are needed to identify physiological or critical care factors following burn injury that contribute to compromise in the structural and functional properties of the airway epithelium.

Chorioamniotic membrane senescence: a signal for parturition?

OBJECTIVE: Senescence is an important biological phenomenon involved in both physiologic and pathologic processes. We propose that chorioamniotic membrane senescence is a mechanism associated with human parturition. The present study was conducted to explore the association between senescence and normal term parturition by examining the morphologic and biochemical evidences in chorioamniotic membranes. STUDY DESIGN: Chorioamniotic membranes were collected from normal term deliveries; group 1: term labor and group 2: term, not in labor. Senescence-related morphologic changes were determined by transmission electron microscopy and biochemical changes were studied by senescence-associated (SA) ß-galactosidase staining. Amniotic fluid samples collected from both term labor and term not in labor were analyzed for 14 SA secretory phenotype (SASP) markers. RESULTS: Morphologic evidence of cellular senescence (enlarged cells and organelles) and a higher number of SA ß-galactosidase-stained amnion and chorion cells were observed in chorioamniotic membranes obtained from women in labor at term, when compared to term not in labor. The concentration of proinflammatory SASP markers (granulocyte macrophage colony-stimulating factor, interleukin-6 and -8) was significantly higher in the amniotic fluid of women in labor at term than women not in labor. In contrast, SASP factors that protect against cell death (eotaxin-1, soluble Fas ligand, osteoprotegerin, and intercellular adhesion molecule-1) were significantly lower in the amniotic fluid samples from term labor. CONCLUSION: Morphologic and biochemical features of senescence were more frequent in chorioamniotic membranes from women who experienced term labor. Senescence of chorioamniotic membranes were also associated with amniotic fluid SASP markers.

Pulmonary histopathologic abnormalities and predictor variables in autopsies of burned pediatric patients.

UNLABELLED: Pulmonary abnormalities occur in 30-80% of fatalities after burn. The objective of our study is to investigate lung pathology in autopsy tissues of pediatric burn patients. METHODS: Three scientists with pathology training in pediatric burn care reviewed masked autopsy slides of burned children who died after admission to a burn center from 2002 to 2012 (n=43). Autopsy lung tissue was assigned scores for histologic abnormalities in 9 categories, including alveolar and interstitial fibrosis, hyaline membranes, and type II epithelial cell proliferation. Scores were then tested for correlation with age, TBSA burn, number of days between burn and death, time between burn and admission, and the presence of inhalation injury using analyses with linear models. RESULTS: Type II epithelial cell proliferation was significantly more common in cases with a longer time between burn and admission (p<0.02). Interstitial fibrosis was significantly more severe in cases with longer survival after burn (p<0.01). The scores for protein were significantly higher in cases with longer survival after burn (p<0.03). Enlarged air spaces were significantly more prominent in cases with longer survival after burn (p<0.01), and in cases with the presence of inhalation injury (p<0.01). CONCLUSIONS: Histological findings associated with diffuse alveolar damage (DAD), which is the pathological correlate of the acute respiratory distress syndrome (ARDS), were seen in approximately 42% of autopsies studied. Protein-rich alveolar edema, which is the abnormality that leads to ARDS, may occur from multiple causes, including inhalation injury.

Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans.

Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT(+)) men and five BAT-negative (BAT(-)) men under thermoneutral conditions and after prolonged (5-8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT(+) group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans.

Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia.

BACKGROUND: Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS. METHODS: Adult sheep (30-40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live Pseudomonas aeruginosa (2.5×10(11) CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer's solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5×10(6) hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10×10(6) hMSCs/kg, n=4. RESULTS: By 24 h, the PaO2/FiO2 ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO2/FiO2 of 97±15 mm Hg; lower dose: 288±55 mm Hg (p=0.003); higher dose: 327±2 mm Hg (p=0.003)). The median lung water content was lower in the higher-dose hMSC-treated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9-5.8] vs control: 6.7 g wet/g dry [IQR 6.4-7.5] (p=0.01)). The hMSCs had no adverse effects. CONCLUSIONS: Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS. TRAIL REGISTRATION NUMBER: NCT01775774 for Phase 1. NCT02097641 for Phase 2.

Histological evidence of oxidative stress and premature senescence in preterm premature rupture of the human fetal membranes recapitulated in vitro.

Preterm prelabor rupture of the membranes (pPROM) may lead to preterm births (PTBs). We investigated premature senescence of fetal membranes in women with pPROM and spontaneous PTB with intact membranes (<34 weeks) and the inducibility fetal membrane senescence phenotype by oxidative stress in vitro. IHC was performed for p53, p21, and phospho (p)-p38 mitogen-activated protein kinase (MAPK) as markers of senescence phenotype in pPROM, PTBs, and term births. Term fetal membranes were exposed to cigarette smoke extract to induce oxidative stress. Western blots documented p-p53 and p-p38 MAPK. Transmission electron microscopy assessed cellular morphologic features in clinical and cigarette smoke extract-treated membranes. A total of 80% of pPROM cells and >60% of term cells were positive for all three senescence phenotype markers, and concentrations were higher than in PTBs (P < 0.05). p53 staining was comparable in membranes from PTB and term birth pregnancies, whereas only <30% and <45% of cells were positive for p21 and p38 MAPK, respectively. In vitro cigarette smoke extract exposure increased p-p38 MAPK without any detectable change in p-p53 MAPK. Enlargement of organelles consistent with senescence phenotype was evident in pPROM and term membranes in vivo and after cigarette smoke extract treatment in vitro but was less apparent in PTBs. Histologic and biochemical resemblance of pPROM and term membranes suggests premature senescence of the membranes is a mechanistic feature in pPROM, and this can be phenocopied in an in vitro model.

Four miniature kidneys: supernumerary kidney and multiple organ system anomalies.

More than 350 years after Martius's first reported case in 1656, supernumerary kidney (SNK) continues to fascinate the world of medicine, generating new ideas in the domain of embryogenesis. Association of a normal kidney with a second or third ipsilateral smaller kidney is an extremely rare anomaly with only a total of 81 cases reported until today. We are reporting a case of SNK, clinically diagnosed as right hydronephrosis, associated with an ipsilateral ectopic ureter, a contralateral partially duplicated ureter, and a multiseptate gallbladder. Pathologic examination of the nephrectomy revealed 4 miniature kidneys, joining a dilated ureter through 4 separate conduits. Our patient is the first reported case of SNK with absent ipsilateral normal kidney, presence of more than 3 kidneys on 1 side, and associated anomaly in the gallbladder. This case represents a unique combination of rarities, suggesting insights in the domain of molecular embryology.