Insulin-like growth factor (IGF) and hepatocyte growth factor (HGF) in follicular fluid cooperatively promote the oncogenesis of high-grade serous carcinoma from fallopian tube epithelial cells: Dissection of the molecular effects.

Incessant ovulation is believed to be a potential cause of epithelial ovarian cancer (EOC). Our previous investigations have shown that insulin-like growth factor (IGF2) and hepatocyte growth factor (HGF) in the ovulatory follicular fluid (FF) contributed to the malignant transformation initiated by p53 mutations. Here we examined the individual and synergistic impacts of IGF2 and HGF on enhancing the malignant properties of high-grade serous carcinoma (HGSC), the most aggressive type of EOC, and its precursor lesion, serous tubal intraepithelial carcinoma (STIC). In a mouse xenograft co-injection model, we observed that FF co-injection induced tumorigenesis of STIC-mimicking cells, FE25. Co-injection with IGF2 or HGF partially recapitulated the tumorigenic effects of FF, but co-injection with both resulted in a higher tumorigenic rate than FF. We analyzed the different transformation phenotypes influenced by these FF growth signals through receptor inhibition. The IGF signal was necessary for clonogenicity, while the HGF signal played a crucial role in the migration and invasion of STIC and HGSC cells. Both signals were necessary for the malignant phenotype of anchoring-independent growth but had little impact on cell proliferation. The downstream signals responsible for these HGF activities were identified as the tyrosine-protein kinase Met (cMET)/mitogen-activated protein kinase and cMET/AKT pathways. Together with the previous finding that the FF-IGF2 could mediate clonogenicity and stemness activities via the IGF-1R/AKT/mammalian target of rapamycin and IGF-1R/AKT/NANOG pathways, respectively, this study demonstrated the cooperation of the FF-sourced IGF and HGF growth signals in the malignant transformation and progression of HGSC through both common and distinct signaling pathways. These findings help develop targeted prevention of HGSC.

Effect of ovulation IGF and HGF signaling on the oncogenesis of murine epithelial ovarian cancer cell ID8.

The incidence and mortality of epithelial ovarian cancer (EOC) are increasing in Taiwan and worldwide. The prognosis of this disease has improved little in the last few decades due to insufficient knowledge of the etiology. Previous studies on the role of ovulation in the development of EOC have unveiled IGF2, HGF, and other carcinogens in ovulatory follicular fluid (FF) that exert transformation activities on the exposed fallopian tube fimbria epithelium. However, an orthotopic proof in an animal model is lacking. By using the murine ID8 EOC cells and the syngenic transplantation model, this study explored the effect of FF on the oncogenesis of mouse ovarian cancer. We found FF promoted clonogenicity and anchorage-independent growth of ID8 cells, largely through the IGF-1R and cMET signaling. In contrast, FF modestly promoted cell proliferation independent of the two signals and did not affect cell migration and invasion. Transplantation of ID8 cells into the ovarian bursa of C57BL6/J mice orthotopically grew ovarian tumors and metastasized to the peritoneum with ascites formation. The tumorigenic rate and severity of the disease were positively correlated with the level of IGF-1R and cMET receptors on the cell surface. Our data demonstrated that ovulation, through the signaling of IGF/IGF-1R and HGF/cMET, promotes oncogenic phenotypes in a murine EOC model. The results provide further proof of the carcinogenic effect of ovulation in the development of EOC.

Pathology-supported genetic testing as a method for disability prevention in multiple sclerosis (MS). Part II. Insights from two MS cases.

In Part I of this Review we evaluated the scientific evidence for a Metabolic Model of multiple sclerosis (MS). Part II outlines the implementation of an adaptive pathology-supported genetic testing (PSGT) algorithm aimed at preventing/reversing disability in two illustrative MS cases, starting with a questionnaire-based risk assessment, including family history and lifestyle factors. Measurement of iron, vitamin B12, vitamin D, cholesterol and homocysteine levels identified biochemical deficits in both cases. Case 1, after following the PSGT program for 15 years, had an expanded disability status scale (EDSS) of 2.0 (no neurological sequelae) together with preserved brain volume on magnetic resonance imaging (MRI). A novel form of iron deficiency was identified in Case 1, as biochemical testing at each hospital submission due to MS symptoms showed low serum iron, ferritin and transferrin saturation, while hematological status and erythrocyte sedimentation rate measurement of systemic inflammation remained normal. Case 2 was unable to walk unaided until her EDSS improved from 6.5 to 4.0 over 12 months after implementation of the PSGT program, with amelioration of her suboptimal biochemical markers and changes to her diet and lifestyle, allowing her to regain independence. Genotype-phenotype correlation using a pathway panel of functional single nucleotide variants (SNVs) to facilitate clinical interpretation of whole exome sequencing (WES), elucidated the underlying metabolic pathways related to the biochemical deficits. A cure for MS will remain an elusive goal if separated from nutritional support required for production and maintenance of myelin, which can only be achieved by a lifelong investment in wellness.

Mackay Heart Failure Study: Examining the Root Causes, Compliance With Guideline-Based Therapy and Prognosis.

INTRODUCTION: Heart failure patients have poor outcomes comparable to some malignancies; however, the modern guideline directed medical therapy (GDMT) has improved its outcomes. The clinical characteristics and prescribers' compliance with GDMT for heart failure patients have not been studied in the Mackay region. METHODS: A retrospective cohort study of 115 consecutive adult heart failure patients was conducted at our institution. RESULTS: The study cohort consisted of 80% (n=92) males. Ischaemia was the leading cause accounting for 54% (n=62) of the cohort, followed by idiopathic cardiomyopathy at 32% (n=37). Drug-induced and Takotsubo cardiomyopathies were responsible for 11% and 1% respectively. Two (2) patients (2%) had valvular heart disease. Hypertension was present in 57% while diabetes and atrial fibrillation were present in 32% and 43% of patients. Fifty-nine per cent (59%) had a smoking history. All, except four patients, had reduced left ventricular ejection fraction (LVEF <50%) at diagnosis. Among patients with coronary ischaemia, 37% and 31% were revascularised with percutaneous coronary interventions and bypass graft surgeries, respectively. Renin-angiotensin-aldosterone system inhibitors and beta blockers were prescribed in 94% and 95% of the patients, respectively. Mineralocorticoid inhibitors were used in 25% while ivabradine was given to 8% of patients. Nine per cent (9%) of patients received cardiac resynchronisation therapy. Most patients had improvement in functional class and LVEF during follow-up. There were very few mortalities at 3% (n=3) at the median follow-up of 403 (IQR 239-896) days. CONCLUSION: Our study has shed light on heart failure epidemiology in the Mackay region. We found excellent compliance with GDMT and good prognosis for most patients in terms of both symptom and survival.

Cloning, expression, identification and characterization of borneol dehydrogenase isozymes in Pseudomonas sp. TCU-HL1.

Borneol is a bicyclic plant monoterpene. It can be degraded by soil microorganisms through the conversion of borneol dehydrogenase (BDH) and a known camphor degradation pathway. Recombinant BDH from Pseudomonas sp. TCU-HL1 was produced in the form of inclusion body. The refolded BDH1 tends to precipitate. Insoluble recombinant BDH1 was converted into a soluble form by adding glycerol in LB medium. The kcat and kcat/Km values of soluble form BDH1 for (+)-borneol turned out to be about 34-fold and 45-fold higher, respectively, than those of the refolded enzyme. On the other hand, a gene knockout mutant, TCU-HL1Δbdh, was constructed to investigate the possible presence of a second copy of the bdh gene in TCU-HL1 genome. A new gene, bdh2, encoding a BDH isozyme, was identified, and the recombinant BDH2 protein was produced in a soluble form. Both bdh1 and bdh2 genes are expressed in the crude extract of wild type TCU-HL1, as shown by RT-qPCR results. Both BDH isozymes prefer to degrade (+)-borneol, rather than (-)-borneol, probably because (+)-camphor is the main form present in nature.

Association between body mass index and ready-to-eat food consumption among sedentary staff in Nay Pyi Taw union territory, Myanmar.

BACKGROUND: Ready-to-eat (RTE) food consumption has become popular in the working community with the increase in full-time jobs and the limited time to prepare food. Although RTE food is essential for this community, its consumption causes obesity. In Myanmar, obesity is a modifiable risk factor for non-communicable diseases, causing increases in morbidity and mortality. This study aimed to identify the association between body mass index (BMI) and RTE food consumption among sedentary staff in Nay Pyi Taw Union Territory, Myanmar. METHODS: A cross-sectional study was conducted in 2018, in which 400 respondents participated in face-to-face interviews. The study area was selected using simple random sampling and drawing method. Measuring tape and digital weighing scale were used to measure the height and weight of the respondents. BMI was calculated by dividing the weight by height squared (kg/m2). Overweight and obesity were categorized by World Health Organization cut-off points. The collected data were analyzed using multiple logistic regression to estimate the adjusted odds ratio (AOR), and the 95% confidence interval (CI). RESULTS: This study revealed that sedentary staff who consumed RTE food once or more per month were nearly five times more likely to be overweight and obese (AOR = 4.78, 95% CI 1.44-15.85) than those who consumed RTE food less frequently. In addition, five factors namely being older than 32 years (AOR = 3.97, 95% CI 1.82-8.69), preference for RTE food (AOR = 8.93, 95% CI 2.54-31.37), light-intensity of physical exercise (AOR = 3.55, 95% CI 1.63-7.73), sedentary leisure activities (AOR = 3.32, 95% CI 1.22-9.03), and smoking (AOR = 5.62, 95% CI 1.06-29.90) were positively associated with overweight and obesity. CONCLUSION: Frequent consumers of RTE food and less physically active sedentary staff were more likely to be overweight and obese. This study highlights the urgent need to raise awareness regarding healthy lifestyle behaviors among the working community to reduce the burden of obesity-related chronic diseases. Moreover, sedentary workers should be aware of the food-based dietary guidelines of the country. Policy makers should strictly enforce nutritional labeling of RTE food, and strictly prohibit over-branding of RTE food.

Resolution of isoborneol and its isomers by GC/MS to identify "synthetic" and "semi-synthetic" borneol products.

Borneol is a plant terpene commonly used in traditional Chinese medicine. Optically pure (+)-borneol and (-)-borneol can be obtained by extraction from the plants Dipterocarpaceae and Blumea balsamifera, respectively. "Synthetic borneol" is obtained from the reduction of (±)-camphor to lead to four different stereoisomers: (+)-isoborneol, (-)-isoborneol, (+)-borneol, and (-)-borneol. In contrast, "semi-synthetic borneol" is produced from the reduction of natural camphor, (+)-camphor, to afford two isomers: (-)-isoborneol and (+)-borneol. We established a convenient method to identify them by treating the four stereoisomers with two chiral reagents, (R)-(+)-α-methoxy-α-trifluoromethylphenylacetyl chloride ((R)-(+)-MTPA-Cl) and (1S)-(-)- camphanic chloride. The resulting derivatives from the above mentioned method were analyzed by gas chromatography. The enantiomers of (+)- and (-)-isoborneol were successfully separated from (+)- and (-)-borneol isomers in this study to make this a useful method in the identification of "synthetic" and "semi-synthetic" borneols. Furthermore, we also examined five different commercial borneols. During this course, a novel and unprecedented partial epimerization from isoborneol-camphanic ester to borneol-camphanic ester was observed. However, this phenomenon did not occur in isoborneol-MTPA esters epimerization to borneol-MTPA case under the same conditions. The DFT calculation of activation energies for both reactions was in a good agreement with the results obtained from GC analysis.

Borneol Dehydrogenase from Pseudomonas sp. Strain TCU-HL1 Catalyzes the Oxidation of (+)-Borneol and Its Isomers to Camphor.

Most plant-produced monoterpenes can be degraded by soil microorganisms. Borneol is a plant terpene that is widely used in traditional Chinese medicine. Neither microbial borneol dehydrogenase (BDH) nor a microbial borneol degradation pathway has been reported previously. One borneol-degrading strain, Pseudomonas sp. strain TCU-HL1, was isolated by our group. Its genome was sequenced and annotated. The genome of TCU-HL1 consists of a 6.2-Mbp circular chromosome and one circular plasmid, pTHL1 (12.6 kbp). Our results suggest that borneol is first converted into camphor by BDH in TCU-HL1 and is further decomposed through a camphor degradation pathway. The recombinant BDH was produced in the form of inclusion bodies. The apparent Km values of refolded recombinant BDH for (+)-borneol and (-)-borneol were 0.20 ± 0.01 and 0.16 ± 0.01 mM, respectively, and the kcat values for (+)-borneol and (-)-borneol were 0.75 ± 0.01 and 0.53 ± 0.01 s-1, respectively. Two plant BDH genes have been reported previously. The kcat and kcat/Km values of lavender BDH are about 1,800-fold and 500-fold lower, respectively, than those of TCU-HL1 BDH. IMPORTANCE: The degradation of borneol in a soil microorganism through a camphor degradation pathway is reported in this study. We also report a microbial borneol dehydrogenase. The kcat and kcat/Km values of lavender BDH are about 1,800-fold and 500-fold lower, respectively, than those of TCU-HL1 BDH. The indigenous borneol- and camphor-degrading strain isolated, Pseudomonas sp. strain TCU-HL1, reminds us of the time 100 years ago when Taiwan was the major producer of natural camphor in the world.

A new word embedding model integrated with medical knowledge for deep learning-based sentiment classification.

The development of intelligent systems that use social media data for decision-making processes in numerous domains such as politics, business, marketing, and finance, has been made possible by the popularity of social media platforms. However, the utilization of textual data from social media in the healthcare management industry is still somewhat limited when it is compared to other industries. Investigating how current machine learning and natural language processing technologies can be used in the healthcare industry to gauge public sentiment is an important study. Earlier works on healthcare sentiment analysis have utilized traditional word embedding models trained on the general and medical corpus. However, integration of medical knowledge to pre-trained word embedding models has not been considered yet. Word embedding models trained on the general corpus led to the problem of lacking medical knowledge and the models trained on the small size of the medical corpus have limitations in capturing semantic and syntactic properties. This research proposes a new word embedding model named Word Embedding Integrated with Medical Knowledge Vector (WE-iMKVec). The proposed model integrates sentiment lexicons and medical knowledgebases into the pre-trained word embedding to enrich the properties of word embedding. A new medical-aware sentiment polarity score is proposed for the utilization in learning neural-network sentiment and these vectors incorporate with the original pre-trained word vectors. The resulting vectors are enriched with lexicon vectors and the medical knowledge vectors: Adverse Drug Reaction (ADR) vector and Unified Medical Language System (UMLS) vector are used to build the proposed WE-iMKVec model. WE-iMKVec is validated on the five different social media healthcare review datasets and the empirical results showed its superiority over traditional word embedding models in medical sentiment analysis. The highest improvement can be found in the patients.info medical condition dataset where the proposed model outperforms three conventional word2vec models (Google-News, PubMed-PMC, and Drug Reviews) by 12.7 %, 31.4 %, and 25.4 % respectively in terms of F1 score.

Serum-free light chain test utilisation at a South African academic laboratory and comparison with serum protein electrophoresis results.

Background: Serum protein electrophoresis (SPE), urine protein electrophoresis and immunofixation electrophoresis were traditionally utilised for the diagnosis of monoclonal gammopathies. The quantitative serum-free light chain (SFLC) assay is reportedly more sensitive and has been introduced to recent clinical guidelines. Objective: This study aimed to investigate SFLC test utilisation and describe SPE findings in patients with abnormal SFLC ratios. Methods: A retrospective audit of SFLC analyses was conducted in Cape Town, South Africa, from May 2018 to April 2020. Agreement between abnormal SFLC ratios and SPE results was determined in a sub-group of patients screened for monoclonal gammopathies. Serum-free light chains were analysed using Freelite® Kappa and Lambda assays. Results: Of the 1425 patients included in the audit, 741 (52%) had abnormal SFLC ratios; 636 (45%) had increased and 105 (7%) had decreased SFLC ratios. In a sub-group analysis of 117 new patients with an abnormal SFLC ratio, 57 had a monoclonal protein (M-protein) on SPE (49%), and 60 (51%) did not. Four out of 60 patients without M-protein had a plasma cell dyscrasia, while renal impairment or inflammatory response accounted for the rest. Of the 57 patients with a M-protein and abnormal SFLC ratio, 41 (72%) had a plasma cell dyscrasia, seven (12%) had lymphomas and nine patients (16%) were unclassifiable. Conclusion: Serum-free light chains should be requested when there is a high index of clinical suspicion. Neither SFLC nor SPE should be performed in isolation when screening patients for monoclonal gammopathy, to ensure that no patient is missed. What this study adds: The study adds to the evidence on SFLC test utilisation. Serum protein electrophoresis alone may miss cases of light chain myeloma, while SFLC performed in isolation may produce false positive results in the setting of inflammatory disorders or renal impairment, leading to unnecessary further investigation.

The Double Engines and Single Checkpoint Theory of Endometriosis.

Endometriosis is a chronic disease characterized by the ectopic localization of the endometrial tissue in the peritoneal cavity. Consequently, it causes local pathological changes and systemic symptoms, affecting at least one in every ten women. This disease is difficult to diagnose early, it is prone to dissemination, is difficult to eradicate, tends to recur, and is regarded as "a cancer of no kill". Indeed, the development of endometriosis closely resembles that of cancer in the way of mutagenesis, pelvic spreading, and immunological adaptation. While retrograde menstruation has been regarded as the primary cause of endometriosis, the role of ovulation and menstrual stimuli in the development of endometriosis has long been overlooked. The development of ovarian and peritoneal endometrioses, similar to the development of high-grade serous carcinoma in the fallopian tube fimbriae with intraperitoneal metastasis, depends highly on the carcinogens released during ovulation. Moreover, endometriosis carries an extremely hypermutated genome, which is non-inferior to the ultra-mutated endometrial cancer. The hypermutation would lead to an overproduction of new proteins or neoantigens. Because of this, the developing endometriosis may have to turn on the PD-1/PDL-1 "self-tolerance" checkpoint to evade immune surveillance, leaving an Achilles tendon for an immune checkpoint blockade. In this review, we present the double engines and single checkpoint theory of the genesis of endometriosis, provide the current pieces of evidence supporting the hypothesis, and discuss the new directions of prevention and treatment.

Two Cases of Methimazole-Induced Agranulocytosis With Their Risk Factors.

Background: Antithyroid drugs, such as methimazole (MMI), are standard therapies for the medical management of thyrotoxicosis. Agranulocytosis is a rare but lethal adverse effect of antithyroid medications. We have reported 2 cases of MMI-induced agranulocytosis with similar risk factors that likely predisposed them to this adverse reaction. Case Report: Case 1 involved a 71-year-old woman, with a history of Graves disease, who presented with an altered mental status. She was recently discharged on 40 mg of MMI twice daily, and she continued this dose for 2 months. She was readmitted and found to have neutropenic fever in the setting of MMI-induced agranulocytosis. MMI was discontinued, and she was started on filgrastim. Her cell counts gradually improved, and she was subsequently discharged.Case 2 involved a 68-year-old woman, with a history of Graves disease, who presented with severe back pain, nausea, and vomiting. She was recently discharged on 10 mg of MMI twice daily, which was increased to 10 mg 3 times a day. She was readmitted to the hospital because of a septic shock in the setting of pneumonia, colitis, bacteremia, and MMI-induced agranulocytosis. A bone marrow biopsy showed a polyclonal infiltrate with up to 85% plasma cells. Despite treatment with antibiotics, filgrastim, and continuous renal replacement therapy, she ultimately passed away. Discussion: Although these cases had differing outcomes, they shared similar features and risk factors, including older age, female sex, and relatively higher doses of MMI. Conclusion: Close follow up and awareness of risk factors, such as age, female sex, and higher doses of MMI, may decrease the risk of MMI-induced agranulocytosis and fatal outcomes.

Acute kidney injury without need for dialysis, incidence, its impact on long-term stroke survival and progression to chronic kidney disease.

INTRODUCTION: Patients who had a stroke are at increased risk of sepsis, dehydration and fluctuations in blood pressure, which may result in acute kidney injury (AKI). The impact of AKI on long-term stroke survival has not been studied well. OBJECTIVE: We aimed to identify incidence of AKI during acute stroke, follow-up period and its impact on long-term survival and development of chronic kidney disease (CKD). DESIGN, SETTING AND PARTICIPANTS: Retrospective analysis of patients who had a stroke admitted at the rehabilitation facility in Changi General Hospital, Singapore, between June 2008 and May 2017, with median follow-up of 141 (95% CI 120 to 163) months. OUTCOME MEASURES AND RESULTS OF UNIVARIATE ANALYSIS: Total 681 patients, median age (63.6) years, 173 (28%) died during follow-up. Elevated blood urea (3.02, 95% CI 2.17 to 4.22; p≤0.001) and creatinine (1.96, 95% CI 1.50 to 2.57; p≤0.001) during stroke affected survival adversely.Excluding patients with CKD, we analysed the remaining 617 patients. AKI was noted in 75 (12.15%) patients during the index admission, and it affected survival adversely (2.16, 95% CI 1.49 to 3.13; p<0.001). Of the patients with AKI, 21 of 75 (28%) progressed to CKD over a median follow-up of 40.7 months. CONCLUSIONS: We found AKI during stroke admission was associated with increased mortality as compared with those without AKI on univariate analysis. AKI without need of renal replacement therapy was also associated with progression to CKD in this cohort. This suggests that patients with AKI need to have their renal function monitored longitudinally for development of CKD.

Clinical outcomes after intracorneal ring segment implantation for keratoconus management in corneas with mild apical haze.

PURPOSE: The implantation of intracorneal ring segments represents an effective and safe therapeutic option for visual improvement in patients with keratoconus. The presence of corneal opacities is considered an exclusion criterion for this operation. METHODS: This is a retrospective cohort study of six eyes of six keratoconus patients at Queen Victoria Hospital, East Grinstead, UK, between January 2012 and December 2016. Femtosecond laser-assisted intracorneal ring segment implantation was performed in six eyes with apical corneal haze. Preoperative and postoperative visual acuity, keratometry readings, as well as corneal pachymetry were compared at 6-month follow-up. RESULTS: Uncorrected visual acuity (UCVA) [LogMAR] improved significantly from median 1.05 [95% confidence interval (CI): 0.83-0.13] preoperatively to 0.9 (95% CI: 0.63-1.00) at 6 months postoperatively (p = 0.03). Corrected visual acuity (CDVA) also improved significantly from median 0.75 (95% CI: 0.43-1.00) preoperatively to 0.4 (95% CI: 0.23-0.50) at 6 months postoperatively (p = 0.03). Keratometric readings, K-max (diopters) and K-mean (diopters), decreased significantly from 54.5 and 47.85 preoperatively to 53.45 and 46.42 postoperatively, respectively (p = 0.03). Corneal pachymetry showed no significant changes postoperatively. CONCLUSION: The results of this study show that the presence of apical haze should not exclude the implantation of intracorneal ring segments in patients with keratoconus.

Prevalence and risk factors of anxiety and depression among the community-dwelling elderly in Nay Pyi Taw Union Territory, Myanmar.

Providing elderly mental healthcare in Myanmar is challenging due to the growing elderly population and limited health resources. To understand common mental health problems among Myanmar elderly, this study explored the prevalence and risk factors of anxiety and depression among the elderly in the Nay Pyi Taw Union Territory, Myanmar. A cross-sectional study was conducted among 655 elderly by face-to-face interviews with a pretested questionnaire. Descriptive analysis and multiple logistic regression analyses were performed. The prevalence of anxiety and depression were 39.4% (33.5% for males and 42.4% for females) and 35.6% (33.0% for males and 36.9% for females), respectively. The adjusted odds ratio of having anxiety was significant for having low education level, having comorbidity, having BMI < 21.3, poor dental health, no social participation, and having no one to consult regarding personal problems, while that of having depression was significant for having comorbidity, having BMI < 21.3, poor vision, and having no one to consult regarding personal problems. The reported prevalence of anxiety and depression indicate the demand for mental healthcare services among Myanmar elderly. Myanmar needs to improve its elderly care, mental healthcare, and social security system to reflect the actual needs of its increasing elderly population. Screening for anxiety and depression among elderly with comorbidities should be promoted. Raising community awareness of mental health, encouraging social participation, and supportive counselling are also essential in combating anxiety and depression among Myanmar elderly.

Globe-sparing surgery for medial canthal Basal cell carcinoma with anterior orbital invasion.

PURPOSE: To describe a case series of patients with anterior orbital invasion by medial canthal basal cell carcinoma (BCC) managed with non-exenterating surgery. DESIGN: International, multicenter, retrospective, noncomparative, consecutive case series. PARTICIPANTS: Twenty patients identified from the individual institutions' databases with histologically confirmed orbital invasion by periocular BCC. METHODS: Examination of charts, relevant imaging, and histopathologic data. MAIN OUTCOME MEASURES: Demographics; clinical characteristics and radiologic features; histopathologic features; surgical techniques for excision, reconstruction, and subsequent procedures; complications; visual acuity; and recurrence. RESULTS: Twenty patients were identified. Twelve of 20 patients (60%) had recurrent BCCs, with 1 patient having had prior radiotherapy for previously incomplete excision. Eighteen of 20 patients (90%) had a palpable mass, 16 of 20 patients (80%) had clinical involvement of the nasolacrimal system, and 1 of 20 patients (5%) had limited extraocular movements. Preoperative radiologic evidence of orbital invasion was found in 10 of 20 patients (50%). Histologic evidence of orbital invasion was present in every patient, the subtypes being infiltrative (9/20, 45%), nodular (4/20, 20%), micronodular (2/20, 10%), multifocal (1/20, 5%), and mixed (4/20, 20%); extratumoral perineural invasion was present in 1 patient (5%). Final margins were clear in 18 of 20 patients (90%), positive in 1 of 20 patients (5%), and unclear in 1 of 20 patients (5%). Reconstruction was by direct closure in 1 patient and by a variety of standard oculoplastic flaps and grafts in 19 of 20 patients (95%). Twelve of 20 patients (60%) had postoperative extraocular muscle movement restriction, and 15 of 20 patients (75%) had epiphora. Subsequent revision procedures were needed in 12 of 20 patients (60%), including insertion of a lacrimal bypass tube and revision of medial canthal position. At a mean follow-up of 38 months, 18 of 20 patients (90%) were still alive (2 deaths due to other causes) with 1 recurrence (exenterated). Postoperative visual acuity was within 2 Snellen lines of preoperative visual acuity in 17 of 20 patients (85%). CONCLUSIONS: With careful planning and margin control, conservative surgery in this highly selected group proved possible with a low rate of disease recurrence, albeit with a relatively short follow-up. Postoperative complications, such as epiphora and ophthalmoplegia, were largely expected; most patients underwent subsequent revision procedures to address these and other complications. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Human neutrophil peptides and phagocytic deficiency in bronchiectatic lungs.

RATIONALE: A well-known clinical paradox is that severe bacterial infections persist in the lungs of patients with cystic fibrosis (CF) despite the abundance of polymorphonuclear neutrophils (PMN) and the presence of a high concentration of human neutrophil peptides (HNP), both of which are expected to kill the bacteria but fail to do so. The mechanisms remain unknown. OBJECTIVES: This study examined several possible mechanisms to understand this paradox. METHODS: PMN were isolated from sputum and blood of subjects with and without CF or non-CF bronchiectasis for phagocytic assays. HNP isolated from patients with CF were used to stimulate healthy PMN followed by phagocytic tests. MEASUREMENTS AND MAIN RESULTS: PMN isolated from the sputum of the bronchiectatic patients display defective phagocytosis that correlated with high concentrations of HNP in the lung. When healthy PMN were incubated with HNP, decreased phagocytic capacity was observed in association with depressed surface Fc gamma RIII, actin-filament remodeling, enhanced intracellular Ca(2+), and degranulation. Treatment of PMN with an intracellular Ca(2+) blocker or alpha1-proteinase inhibitor to attenuate the activity of HNP largely prevented the HNP-induced phagocytic deficiency. Intratracheal instillation of HNP in Pallid mice (genetically deficient in alpha1-proteinase inhibitor) resulted in a greater PMN lung infiltration and phagocytic deficiency compared with wild-type mice. CONCLUSIONS: HNP or PMN alone exert antimicrobial ability, which was lost as a result of their interaction. These effects of HNP may help explain the clinical paradox seen in patients with inflammatory lung diseases, suggesting HNP as a novel target for clinical therapy.