Subserosal adenomyotic cysts and peritoneal inclusion cysts - Unusual differential diagnoses of multicystic pelvic masses: A review of two cases.

BACKGROUND: Multiloculated pelvic cysts are commonly misdiagnosed as ovarian tumors or malignancies. We report 2 patients diagnosed with subserosal adenomyotic cysts and peritoneal inclusion cysts, mimicking multiloculated pelvic tumors. We discuss their clinical presentation, investigations, operation findings, and histopathology, present a literature review. CASES: Case 1 was a 44-year-old patient with abnormal uterine bleeding. Imaging showed an enlarging multiloculated cystic structure over the right uterine wall. She underwent a diagnostic laparoscopy and right salpingo-ophorectomy. Intra-operatively, she was found to have multiple subserosal uterine cysts, diagnosed as adenomyotic cysts on histology.Case 2 was a 50-year-old patient with history of laparoscopic cystectomy done 20 years ago. She was incidentally found to have a multiloculated cystic lesion in the pelvis. The lesion was located midline, anterior and superior to the uterus and bladder. She underwent a total abdominal hysterectomy, bilateral salpingo-ophorectomy, and bladder peritonectomy. Intra-operatively, multiple cystic lesions were noted over the anterior and fundus of uterus, bladder peritoneum, and pelvic side walls. The condition was confirmed to be peritoneal inclusion cysts on histology. CONCLUSION: Subserosal adenomyotic cysts are a rare presentation of adenomyosis. They typically occur in premenopausal women. Treatment is usually by hormonal medications or surgical excision.Many patients with peritoneal inclusion cysts have a history of peritoneal insults. Surgical excision is the most commonly described management as they often mimic malignancy. Both conditions are unusual presentations of multiloculated pelvic masses. A high recurrence rate is found, hence long-term follow-up with imaging is essential.

Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair.

Endochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation, directed by local morphogen signals and mechanical cues. Here, we aimed to mimic development for regeneration of large bone defects. We hypothesized that engineered human mesenchymal condensations presenting transforming growth factor-ß1 (TGF-ß1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles promotes endochondral defect regeneration contingent on in vivo mechanical cues. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with BMP-2 + TGF-ß1 fully restoring mechanical function. Delayed in vivo ambulatory loading significantly enhanced the bone formation rate in the dual morphogen group. In vitro, BMP-2 or BMP-2 + TGF-ß1 initiated robust endochondral lineage commitment. In vivo, however, extensive cartilage formation was evident predominantly in the BMP-2 + TGF-ß1 group, enhanced by mechanical loading. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.

Percutaneous mechanical thrombectomy in the treatment of acute iliofemoral deep vein thrombosis: a systematic review.

BACKGROUND: Conventional treatment of deep vein thrombosis (DVT) of the lower extremities by anticoagulation alone has been proven to be insufficient to prevent recurrence and post-thrombotic syndrome (PTS). Early restoration of venous patency and preservation of valvular function by endovascular surgery has been advocated. The aim of this study was to review the efficacy and safety of percutaneous mechanical thrombectomy (PMT) against catheter-directed thrombolysis (CDT) in the treatment of acute iliofemoral DVT. METHODS: Three hundred sixty-nine articles were identified through screening of the PubMed, EMBASE, and Cochrane databases from January 2006 to December 2016. RESULTS: Fifteen retrospective studies and one prospective registry, totalling 1170 patients, were recruited for qualitative synthesis. The venous patency rate ranged from 75% to 100% with mean follow-up of 12.3 months. The rates of PTS and recurrent DVT were less than 17% and 15%, respectively. The overall mortality rate was 0.26%. Compared with CDT, PMT was shown to reduce PTS at 1 year (Villalta score: 2.1 ± 3.0 in the PMT group and 5.1 ± 4.1 in the CDT group, P=0.03) and bleeding complications (packed cells transfused: 0.2 ± 0.3 units in the pharmacomechanical thrombectomy group and 1.2 ± 0.7 units in the CDT group, P<0.05). CONCLUSION: Percutaneous mechanical thrombectomy is a safe and effective treatment for acute iliofemoral DVT in terms of restoration of venous patency, prevention of DVT recurrence, and PTS. Compared with CDT alone, PMT offers a lower risk of PTS and bleeding complications.

Hydrogen sulfide protects testicular germ cells against heat-induced injury.

OBJECTIVE: The present study was designed to investigate whether H2S can protect testicular germ cells against heat exposure induced injury and the underlying mechanisms. RESULTS: It was found that all three H2S generating enzymes, cystathionine ß-synthase (CBS), cystathionine γ-lysase (CSE), and 3-mercaptopyruvate sulfurtransferase (3 MST), were expressed in mouse testicular tissue. Three episodes of heat exposure (42 °C, 30 min/day, 3 days) significantly decreased endogenous H2S production and down-regulated the expression of CBS and CSE in testes. In primary cultured testicular germ cells, exogenous application of NaHS (an H2S donor) attenuated heat stress (42 °C, 30 min) induced cell death and apoptosis. This was mediated by the inhibitory effects of H2S on cytochrome C release and the ratio of the Bax/Bcl-2. NaHS also improved mitochondrial function by decreasing oxygen consumption and increasing ATP production. NaHS treatment also stimulated SOD activity and reduced ROS production. CONCLUSIONS: Our results revealed both physiological and pharmacological roles of H2S in testicular germ cells. Exogenous application of H2S may protect germ cells by preservation of mitochondrial function and stimulation of anti-oxidant activity.

Multiple variants aggregate in the neuregulin signaling pathway in a subset of schizophrenia patients.

Despite the strongly held view that schizophrenia (SZ) shows substantial genetic heterogeneity, pathway heterogeneity, as seen in cancer where different pathways are affected in similar tumors, has not been explored. We explore this possibility in a case-only study of the neuregulin signaling pathway (NSP), which has been prominently implicated in SZ and for which there is detailed knowledge on the ligand- and receptor-processing steps through ß- and γ-secretase cleavage. We hypothesize that more than one damaging variants in the NSP genes might be necessary to cause disease, leading to an apparent clustering of such variants in only the few patients with affected NSP. We analyze linkage and next-generation sequencing results for the genes encoding components of the pathway, including NRG1, NRG3, ERBB4, ß-secretase and the γ-secretase complex. We find multiple independent examples of supporting evidence for this hypothesis: (i) increased linkage scores over NSP genes, (ii) multiple positive interlocus correlations of linkage scores across families suggesting each family is linked to either many or none of the genes, (iii) aggregation of predicted damaging variants in a subset of individuals and (iv) significant phenotypic differences of the subset of patients carrying such variants. Collectively, our data strongly support the hypothesis that the NSP is affected by multiple damaging variants in a subset of phenotypically distinct patients. On the basis of this, we propose a general model of pathway heterogeneity in SZ, which, in part, may explain its phenotypic variability and genetic complexity.

Neutralization of the γ-secretase activity by monoclonal antibody against extracellular domain of nicastrin.

Several lines of evidence suggest that aberrant Notch signaling contributes to the development of several types of cancer. Activation of Notch receptor is executed through intramembrane proteolysis by γ-secretase, which is a multimeric membrane-embedded protease comprised of presenilin, nicastrin (NCT), anterior pharynx defective 1 and PEN-2. In this study, we report the neutralization of the γ-secretase activity by a novel monoclonal antibody A5226A against the extracellular domain of NCT, generated by using a recombinant budded baculovirus as an immunogen. This antibody recognized fully glycosylated mature NCT in the active γ-secretase complex on the cell surface, and inhibited the γ-secretase activity by competing with the substrate binding in vitro. Moreover, A5226A abolished the γ-secretase activity-dependent growth of cancer cells in a xenograft model. Our data provide compelling evidence that NCT is a molecular target for the mechanism-based inhibition of γ-secretase, and that targeting NCT might be a novel therapeutic strategy against cancer caused by aberrant γ-secretase activity and Notch signaling.

Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice.

beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. To test this hypothesis, we analyze the behaviors considered to be rodent analogs of clinical features of schizophrenia in BACE1(-/-) mice with impaired processing of NRG1. We demonstrate that BACE1(-/-) mice exhibit deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments, and deficits in social recognition. Importantly, some of these manifestations were responsive to treatment with clozapine, an atypical antipsychotic drug. Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.

Menopause, hormone therapy and cardiovascular and cerebrovascular disease.

INTRODUCTION: Cardiovascular disease is the leading cause of death and morbidity among postmenopausal women, and oestrogen deficiency may be an important factor in its development. The role of oestrogen replacement in preventing cardiovascular disease is controversial. The aim of this descriptive review is to analyse the available data and to recommend evidence-based practice guidelines pertaining to hormone therapy in the context of cardiovascular and cerebrovascular health. MATERIALS AND METHODS: Relevant clinical trials were identified by computerised literature search. The collated data were presented to fellow gynaecologists for review, analysis of results and discussion in a series of meetings dedicated to finding the best evidence in menopause management. The evidence was used to formulate clinical practice guidelines for the management of women with significant cardiovascular risk factors. RESULTS: Evidence from animal studies and observational trials supported a cardio-protective effect of postmenopausal hormone therapy. More recent randomised clinical trial data have shown no significant reduction of coronary heart disease, and have confirmed a higher incidence of stroke and venous thromboembolism. CONCLUSIONS: The evidence is widely divergent regarding postmenopausal hormone therapy and cardiovascular risk. More consistent data are available reporting an increased risk in the incidence of venous thromboembolism and stroke. It is important to be clear about the indications of hormone use and to utilise alternative modalities to promote cardiovascular health in the postmenopausal population.

Polymorphisms of glutathione S-transferase genes and functional activity in smokers with or without COPD.

OBJECTIVE: To determine the role of polymorphisms of genes regulating glutathione S-transferase (GST) and its plasma GST activity in the pathogenesis of chronic obstructive pulmonary disease (COPD). DESIGN: Case-control study. METHODS: One hundred and sixty-three patients with stable COPD from several community or regional hospitals were matched for age and pack-years smoked with the same number of health controls from the general population. Each participant underwent an interview-based respiratory and smoking questionnaire, lung function testing and gave a blood sample. Genotyping was carried out using a polymerase chain reaction-based method for polymorphisms of glutathione S-transferase theta 1 (GSTT1), glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase P 1 (GSTP1) genes. Plasma GST activity was measured using the spectrofluorometric method. RESULTS: There were no significant differences in the distribution of various genotypes of polymorphisms of GSTT1, GSTM1 and GSTP1 between COPD patients and healthy controls. GST activity was significantly higher in patients compared with controls, irrespective of their different genotypes, and was not different between patients with different levels of airflow obstruction. CONCLUSION: Polymorphisms of GSTT1, GSTM1 and GSTP1 genes are unlikely to be involved in the pathogenesis of COPD in Chinese in Hong Kong and Southern China.

The clinical value of autofluorescence bronchoscopy for the diagnosis of lung cancer.

The aim of this study was to evaluate the role of autofluorescence bronchoscopy (AFB) in the routine work-up of lung cancer. Consecutive patients with atypical or suspicious cells in sputum or bronchial aspirate, no localising abnormality on chest radiography and nondiagnostic white-light bronchoscopic (WLB) results were recruited. WLB and AFB were performed sequentially during the same session. All abnormal areas detected by WLB, AFB or both were sampled and the biopsy specimens sent for histological examination. Sixty-two patients were recruited within the 32-month study period. Seventeen had no endobronchial lesion detected. Among the 45 patients with endobronchial lesions, 37 had lesions with a histopathological grade of mild dysplasia or less; of the eight patients who had a lesion with a histological grade of moderate dysplasia or worse, five were found to have lung cancer, two invasive lung cancer and three an intra-epithelial neoplasm (severe dysplasia). Lesions showing moderate dysplasia or worse were more commonly found in patients with suspicious cells than in those with atypical cells on sputum examination. AFB was more sensitive than WLB (91 versus 58%) at detecting these lesions, but less specific (26 versus 50%). A combination of white-light and autofluorescence bronchoscopy can increase the diagnostic yield of this invasive procedure in patients exhibiting abnormal sputum cytology.

Bronchiolitis obliterans organising pneumonia (BOOP) in a lung cancer patient after lobectomy.

A 79 year-old patient with lung cancer underwent a standard thoracotomy and lobectomy. Postoperatively, he developed low-grade fever and dyspnoea. Chest X-rays showed progressive lung infiltrates, which was subsequently diagnosed to be Bronchiolitis Obliterans Organizing Pneumonia (BOOP) by transbronchial lung biopsy. He responded well to corticosteroid therapy. The case report is followed by a brief discussion on BOOP in association with lung cancer and thoracotomy.

Nine-day-old human embryo cultured in vitro: a clue to the origins of embryonic stem cells.

The aims of this study were to investigate whether the human embryo could sustain development beyond the blastocyst stage in vitro and to identify the precise origins of embryonic stem cells (ES cells) from the embryoblast. A frozen-thawed 4-cell embryo was cultured to the post-blastocyst stage. This 9-day-old embryo presented a solid mass of inner cells (resembling a tumour) surrounded by surface trophoblast cells. Clumps of multinucleated syncytiotrophoblast cells were evident at one pole. Most cells resembled those of blastocysts. However, there were groups of comparatively undifferentiated cells within the inner cell mass somewhat resembling ES cells documented previously, that might give a clue as to their origins. The embryo attempted to form an amnion with a cavity, but did not present a bilaminar, discoidal structure as expected in week 2 of development, and hence was abnormal.

Prolonged disturbances of in vitro cytokine production in patients with severe acute respiratory syndrome (SARS) treated with ribavirin and steroids.

Severe acute respiratory syndrome (SARS) is a new disease which has spread rapidly and widely. We wished to know whether evaluation of in vitro cytokine production could contribute to improved understanding of disease pathogenesis and to better patient management. Numbers of unstimulated and mitogen-stimulated cytokine-secreting peripheral blood mononuclear cells were measured repeatedly during and after hospitalization in 13 patients with SARS using enzyme-linked immunospot technology. Numbers of interferon-gamma, interleukin (IL)-2, IL-4, IL-10 and IL-12 secreting cells induced by T cell activators were below normal in many or most patients before and during treatment with corticosteroids and ribavirin but returned essentially to normal after completion of treatment. Staphylococcus aureus Cowan 1 (SAC)-stimulated IL-10 secreting cells were increased in early SARS but fell during treatment. SAC-induced IL-12 secreting cells were deficient before, during and long after treatment. Numbers of cells induced to produce IL-6 and tumour necrosis factor-alpha by T cell or monocyte activators were higher than normal in many early SARS patients and were still increased in some during and after treatment. We conclude that prolonged dysregulated cytokine production occurs in SARS and that future studies should be directed at improving anti-inflammatory and antiviral therapies in order to limit cytokine impairment.

Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues.

The mechanisms leading to neurodegeneration in ALS (amyotrophic lateral sclerosis) are not well understood, but cytosolic protein aggregates appear to be common in sporadic and familial ALS as well as transgenic mouse models expressing mutant Cu/Zn superoxide dismutase (SOD1). In this study, we systematically evaluated the presence of these aggregates in three different mouse models (G93A, G85R, and G37R SOD1) and compared these aggregates to those seen in cases of sporadic and familial ALS. Inclusions and loss of motor neurons were observed in spinal cords of all of these three mutant transgenic lines. Since a copper-mediated toxicity hypothesis has been proposed to explain the cytotoxic gain-of-function of mutant SOD1, we sought to determine the involvement of the copper chaperone for SOD1 (CCS) in the formation of protein aggregates. Although all aggregates contained CCS, SOD1 was not uniformly found in the inclusions. Similarly, CCS-positive skein-like inclusions were rarely seen in ALS neurons. These studies do not provide strong evidence for a causal role of CCS in aggregate formation, but they do suggest that protein aggregation is a common event in all animal models of the disease. Selected proteins, such as the glutamate transporter GLT-1, were not typically observed within the inclusions. Most inclusions were positively stained with antibodies recognizing ubiquitin, proteasome, Hsc70 in transgenic lines, and some Hsc70-positive inclusions were detected in sporadic ALS cases. Overall, these observations suggest that inclusions might be sequestered into ubiquitin-proteasome pathway and some chaperone proteins such as Hsc70 may be involved in formation and/or degradation of these inclusions.

Chronic necrotizing pulmonary aspergillosis. A report of 9 cases with analysis of clinical picture, risk factors and treatment for outcome correlation.

Nine patients with chronic necrotizing pulmonary aspergillosis (CNPA) were analyzed retrospectively. Eight cases had been treated with itraconazole. Four patients had received intravenous amphotericin B (AMB), three sequentially with itraconazole and one as monotherapy. Three patients died after 1, 2 and 24 weeks of therapy. Six responded to therapy and survived 3 to 58 months after treatment. Only the total number of risk factors was found to be statistically significant in relation to a fatal outcome. The mean number of risk factors was 5.33 for fatal cases compared to 2.83 for treatment responders. The presence of five or more risk factors and two individual risk factors, hypoalbuminemia less than 27 g/L and history of dual pulmonary mycobacterioses, were 100% predictive of mortality in our patients. The overall clinical picture of fatal CNPA cases resembles closely that of acute invasive pulmonary aspergillosis in severely immunocompromised subjects.

The value of transgenic models for the study of neurodegenerative diseases.

Transgenic animal models are useful in studying the features of APP- and PS1-linked FAD and SOD1-linked FALS. These models help to investigate the nature of the cellular/biochemical/molecular alterations in neural tissue; the character and evolution of neuronal and/or glial abnormalities; the ways mutant proteins cause damage to neurons; and the biochemical pathways associated with cell death. New technologies will help to define changes in a variety of genes/gene products and the events and conformational changes in mutant proteins that are implicated in pathogenic cascades. It is hoped such study will result in novel treatments for testing in transgenic models that can then be translated into new treatments for human neurodegenerative diseases.

Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection.

Liver toxicity is a common side effect of antituberculosis (anti-TB) drugs. We studied the differences in liver dysfunction observed during anti-TB treatment between hepatitis B virus carriers (HBV) and noncarriers. Three hundred twenty-four patients on anti-TB drugs were recruited and followed up for 1 year. Forty-three patients with HBV and 276 non-HBV patients were included for analysis. Liver function tests and viral markers were monitored monthly. Liver biopsy was requested whenever the alanine transaminase (ALT) was persistently abnormal. Eighty-six HBV carriers who were not given anti-TB drugs were chosen as a second control and evaluated prospectively. The incidence of liver dysfunction was significantly higher in HBV carriers given anti-TB drugs (34.9%) when compared to noncarriers (9.4%, P <.001) and with HBV carriers not given anti-TB drugs (8.1%, P <.001). For patients given anti-TB drugs, HBV carriers who developed liver dysfunction were younger (P =.011) and had more severe liver injury compared with noncarriers (P =.008). By multiple logistic regression analysis, age (P =.002) and hepatitis B infection (P <.001) were the only 2 significant risk factors for hepatotoxicity related to anti-TB therapy.

Impact of respiratory syncytial virus infection on surgery for congenital heart disease: postoperative course and outcome.

OBJECTIVES: a) To describe the postoperative course and outcome of cardiac surgery in children with recent respiratory syncytial virus (RSV) infection; and b) to evaluate whether timing of surgery has any impact on the outcome. DESIGN: Retrospective case series. SETTING: Intensive care unit and medical and surgical wards of a teaching pediatric hospital. PATIENTS: Twenty-five children (aged 25 days to 3.5 yrs; median, 4 months) with congenital heart disease who had cardiac surgery within 6 months after RSV infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We reviewed the clinical course and outcome of all patients. The cardiac diagnoses included ventricular septal defect (n = 11), tetralogy of Fallot (n = 3), atrioventricular canal (n = 3), and others (n = 8). Thirteen patients had surgery during the same admission as RSV infection (group I), and 12 patients had surgery electively after being discharged to home after RSV infection (group II). Two patients in group I died; both of these patients had undergone total repair of tetralogy of Fallot within 2 wks after admission for RSV infection. Postoperative complications in group I patients included pulmonary hypertension (n = 5), adult respiratory distress syndrome (n = 1), tracheal stenosis (n = 1), left ventricular dysfunction (n = 1), pericardial effusion (n = 1), secondary bacterial or fungal infection (n = 7), and deep venous thrombosis (n = 1). Of all group I patients, the ones who were operated on early appeared to be at higher risk for complications, especially for postoperative pulmonary hypertension. No patient in group II died, and only two patients had minor complications (one had reactive airway disease, and the other had a transient superior vena cava syndrome after a bidirectional Glenn operation). CONCLUSIONS: Cardiac surgery performed during the symptomatic period of RSV infection is associated with a high risk of postoperative complications, especially postoperative pulmonary hypertension. These complications appeared to be more frequent and of greater severity in patients who had earlier surgery compared with those who had later surgery. More studies are needed regarding the proper timing of cardiac surgery in patients with congenital heart disease and RSV infection.