NETs, infections, and antimicrobials: a complex interplay.

In response to a range of stimuli, neutrophils produce web-like structures known as neutrophil extracellular traps (NETs). The benefits of NETs in pathogen control are commonly offset by excessive release as part of a pro-inflammatory response, as shown in several disorders. The discovery of potential drugs that regulate NET release has helped to enhance our understanding of the role of NETs in immunological protection, inflammatory diseases, and autoimmune disorders. Emerging evidence has indicated that antimicrobials play an immunomodulatory role by influencing the levels of circulating NETs. Herein, we address NETosis in several disorders and detail the mechanisms of NET-mediated damage in infections. We also aim to evaluate recent evidence on the effects of antimicrobials on NET levels. Relevant keywords were searched in PubMed. Studies were evaluated for their relevance, and a narrative review was written accordingly. Several antibiotics, including beta-lactams and cephalosporins, alter NET formation and degradation in a protective manner, resulting in minimal host organ damage. Additionally, some studies have highlighted the immunomodulatory effects of antivirals and antifungals on NET. Further studies are needed to fully understand the clinical implications of NET-antimicrobial interactions and their underlying mechanisms.

STUDY OF KCNJ11 GENE MUTATIONS IN ASSOCIATION WITH MONOGENIC DIABETES OF INFANCY AND RESPONSE TO SULFONYLUREA TREATMENT IN A COHORT STUDY IN EGYPT.

INTRODUCTION: KCNJ11 gene activating mutations play a major role in the development of neonatal diabetes mellitus (NDM). KCNJ 11 gene encodes the Kir 6.2 subunit of ATP- sensitive potassium channel which is a critical regulator of pancreatic beta-cell insulin secretion. AIM: To study KCNJ11 gene mutations in infants with NDM and the effect of sulfonylurea treatment on the glycemic control in patients with KCNJ11 gene mutation. SUBJECTS AND METHODS: Thirty infants with NDM were screened for KCNJ11 gene mutations by DNA sequencing, insulin therapy was replaced by sulfonylurea treatment in patients with mutations. RESULTS: R201C heterozygous mutation was found in one patient who was successfully shifted from insulin therapy to sulfonylurea treatment, while E23k, I337V, and S385C polymorphisms were detected in 14 patients. CONCLUSION: Screening for KCNJ 11 gene mutations could lead to identification of patients with mutations who can be successfully shifted from insulin therapy to sulfonylurea treatment improving their quality of life.

Autologous translocation of the choroid and RPE in age-related macular degeneration: 1-year follow-up in 30 patients and recommendations for patient selection.

AIM: To evaluate the long-term (1 year) functional and anatomical outcome of autologous translocation of peripheral choroid and retinal pigment epithelium (RPE) in 30 patients with age-related macular degeneration (AMD). METHODS: After the extraction of the neovascular complex, an autologous peripheral full-thickness graft of RPE and choroid was positioned under the macula. Functional tests included ETDRS vision, reading (Radner test), and microperimetry (scanning laser ophthalmoscope). Fluorescein, indocyanine green angiography, and autofluorescence were monitored. RESULTS: Preoperative visual acuity ranged from 20/40 to 20/800 (0.3-1.6 log MAR). Vision ranged from 20/25 to LP (0.1-2.1 log MAR) 1 year after surgery, with stabilization in six eyes, an increase in five eyes, and a decrease in 19 eyes. Deterioration mostly occurred within the first 3 months after surgery. In patients who demonstrated vascularization of the graft after 3 months, this persisted up to 12 months as did fixation when initially stable. Autofluorescence decreased significantly from 6 to 12 months postoperatively. Eleven cases showed a recurrence of choroidal neovascularization (CNV) within this period. CONCLUSION: Patch translocation results in a viable graft. There is no evidence of graft failure within a 1-year follow-up. Nevertheless, there is risk for late CNV formation originating from the edges of the excision side of the CNV and growing peripheral to the graft.

Synthesis of novel dihydropyridine, dihydropyrimidine, dithioacetal and chalcone derivatives from formylchromones.

Condensation of 6-Formylfurochromone (4,9-dimethoxy-5-oxo-5H-furo[3,2-g][1]benzopyran-6-carbaldehyde) 5a and malononitrile without solvent afforded (2E)-2-cyano-3-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]benzopyran-6-yl) acrylamide 8 at hydrolysis with dilute HCL. 2,6-Diamino-4-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g]benzopyran-6-yl)-1,4-dihydropyridine-3,5-dicarbonitrile 9 and 6-(2,6-diacetyl-3,5-dimethylcyclohexa-2,5-dien-1-yl)-4,9-dimethoxy-5H-furo[3,2-g][1]benzopyran-5-one 10a,b were synthesized by one-pot cyclocondensation reaction of formyl 5a, malononitrile and ammonium acetate/or ammonium hydroxide/or aniline. The reaction of formyl 5a, malononitrile/acetylacetone (Thio) urea/guanidine HCL to give 6-amino-4-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g][1]benzopyran-6-yl)-2-methylene-1,2,3,4-tetrahydropyrimidine-5-carbonitrile compounds 11a,b, 6-(2-amino-5,6-dimethyl-1,4-dihydropyrimidin-4-yl)-4,9-dimethoxy-5H-furo[3,2-g][1]benzopyran-5-one 12a,b. Condensation of formylfurochromone 5a with thiol compounds afforded 6-isopropyl-4-methoxy-9-(methoxy Ia or methyl Ib)-5H-furo[3,2-g][1]benzopyran-5-one 13a-f; 6-(1,3-dithiolan-2-yl)-4-methoxy-5H-furo[3,2-g]chromen-5-one 14a,b; 7-hydroxy-6-isopropyl-5-methoxy-2-methyl-4H-benzopyran-4-one 5a-c; 6 hydroxy-7-[mercapto(methylthio)methyl-8-methoxy-3-methylnaphthalen-1(4H)-one 16, respectively. Formylfurochromones 5a-c were reacted with different substituted of acetyl compounds (khellinone, 2-acetyl pyrrol, 3-acetyl coumarin, methyl-2-thienyl ketone and p-aminoacetophenone respectively) to proceed 4-methoxy-9-(methoxy Ia or methyl Ib)-6-(1E)-3-oxobut-1-enyl]-5H-furo[3,2-g][1]benzopyran-5-one 17, 5-methoxy-2-methyl-6[(1E)-3-oxobut-1-enyl]-4a,5,8,8a-tetrahydro-4H-benzopyran-4-one 18a-d, 4,9-dimethoxy-6-[(1E)-3-methoxyprop-1-enyl]-5H-furo[3,2-g][1]benzopyran-5-one-N-methylene-N-phenylamine-6-(iminomethyl)-4,9-dimethoxy-5H-furo[3,2-g][1]benzopyran-5-one 19.

Synthesis and pharmaceutical activity of new series of chromonyl derivatives.

A new synthesis of chromonyl based on the reaction of formylfurochromone (4,9-dimethoxy-5-oxo-5H-furo[3,2-g][1] benzopyran-6-carbaldebyde) 1 with semicarbazide hydrochloride and thiosemicarbazide afforded 4,9-dimethoxy-5-oxo-5H-furo[3,2-gl]][1] benzopyran-6-yl-(1-aminovinyl) hydrazone derivatives 2a,b. Also 4,5-Diphenyl-2-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g][1] benzopyran-6-yl)-imidazole 3 was obtained by refluxing compound 1 with 1,2-diketone in presence of ammonium acetate. Reaction of compound 1 with different amines afforded 3-(4,9-dimethoxy-5-axo-5H-furo[3,2-g][1] benzopyran-6-yl)-aryliminoethyl derivatives 4a-g. Condensation reaction of compounds 4a-d to C-Hacid compounds were given 4-aminosubstituted-5-(6-hydroxy-4,7-dimethoxy-5-axo-5H- benzofuranyl)-pyrano[2,3-b] cyclobexa-2,3-diene 5a-d and 2-methyl-3-methoxy-4-(4-methoxypheny-lamine)-5-(6-hydroxy-4,7- dimethoxy-5-oxo-5H-benzofuranyl) 6. Refluxing compound 4d with thiosemicarbazide formed 6-methanimine-(4,9-dimethoxy-5-axo-5H-furo[3,2-g][1] benzopyran-6-yl)-(1E)-1-phenylethan-1-one thiosemicarbazide 7. Also, the reaction of compound 4d with p-aminoacetophenone gave the aryliminoethyl compound 8. The reaction of compound 4d with different aldehydes were given 3-(4,9-dimethoxy-5-oxo-5H-furo[3,2-g][1] benzopyran)-iminomethyl-(1-aryl-1-oxo-3-proponyl substituted) 9a-d. Condensation of formyl fuorochromone 1 with phenolic compounds yielded 3-(4,9-dimethoxy-5-axo-5H-furo[3,2-g][1] benzopyran-6-yl)-derivatives 10a-d. All the tested compounds a significant increase in PT & APTT when compared with that of the control group. Only the compound IIa treated rats induced significant increase Ast, alkaline phosphatase and urea during experimental period, while other tested compounds did not cause any significant changes in liver and kidney function. Concomitantly, all the tested compound caused a significant decrease in serum cholesterol and triglyceride levels.

A new synthesis of oxadiazole, thiazolidinone, N-phthalimidoamino carbonyl and arylidene derivatives with potential antimicrobial activity.

Condensation of carbohydrazide derivatives Ia, b with dimethyl acetylenedicarboxylate and acetylenedicarboxylic acid yielded benzofuran derivatives II a-d. Reaction of Ib with aromatic aldehydes formed products III a-d. Treatment of compounds III a-d with mercaptoacetic acid yielded the cyclocondensation products (IVa-d). Phthalic anhydride reacted with compounds (Ia, b)to form products (Va, b). It has been found that both khellin and visnagin (VIa, b)react with aromatic aldehydes to give arylidene derivatives (VIIa-e). Condensation of diphenyl nitrilamine with 2-arylidene furochromones VII derivatives afforded cyclo-adducts (VIII a-i). The antibacterial activities of the selected compounds were tested against Staphylococcus aureus, B. subtilis, E. coli, Pseudomonas, Salmonella and Erwinia with good results.

Simple synthesis of condensed pyran containing compounds and their antimicrobial properties.

Reaction of various fused pyran compounds with formic acid was studied. Thus, refluxing 6-aminopyrano[2,3-c]pyrazole-5-carbonitriles 3 with formic acid afforded the corresponding 3-aryl-3-(5-hydroxy-3-methyl-1H-pyrazole-4-yl)propanoic acids 4. Whereas, reaction of formic acid with 2-amino-4H-1-benzopyran-3-carbonitriles 6 gave the corresponding quinoline-2,5(1H,6H)-diones 7. The study was also extended towards many spiro compounds possessing pyran residue. The antimicrobial properties of the prepared compounds was screened.

Synthetic approaches towards benzo[h]quinoline-3-carbonitriles.

2-Alkoxybenzo[h]quinoline-3-carbonitriles 2 were readily synthesized via Dimroth rearrangement of 2-amino-4-aryl-5,6-dihydro-4H-naphtho[1,2-b]pyran-3-carbonitriles 5 induced by ethanolic and methanolic KOH. Compounds 2 were also obtained by the reaction of 2-arylmethylidene-3,4-dihydro-1(2H)-naphthalenones 1 with malononitrile or of ylidenemalononitriles 4 with 1,2,3,4-tetrahydro-1-naphthalenone in ethanolic and methanolic KOH. The molluscicidal activity of the products towards Biomphalaria alexandrina snails was screened.

Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma.

PURPOSE: Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen. PATIENTS AND METHODS: Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days. RESULTS: The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths. CONCLUSION: The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

New 2 H-benz[g]indazoles of anticipated molluscicidal activity.

A facile synthetic approach towards the synthesis of 2-substituted carbamoyl (or thiocarbamoyl)-3-aryl-3,3a,4,5-tetrahydro-2 H-benz[g]indazoles 3a-r and their 2-acylating derivatives 4-6 was reported via the reaction of 2-unsubstituted-2 H-benz[g]indazoles 2 with isocyanates or their thio analogues, acid anhydrides and aliphatic or aromatic carboxylic acids. The molluscicidal activity of the products was screened.

Pyridines and pyrazolines from salicylic acid derivatives with propenone residue and their antimicrobial properties.

Reaction of the propenones 1c, d with chlorosulfonyl isocyanate followed by hydrolysis gave the corresponding carbamoyloxybenzoates 2a, b. While their reaction with ethyl isocyanate afforded the 1,3-benzoxazine-2,4-diones 3a, b. Reaction of 1a, b with aryl hydrazines gave the pyrazolines 4a, d, whereas, with hydrazine hydrate in acetic acid, the acetyl derivatives 4e, f were produced. 1c, d reacted with malononitrile and ethyl cyanoacetate affording the cyanopyridines 5 and cyanopyridones 6 respectively. The products show antimicrobial activities.

A psychoeducational nursing intervention to enhance coping and affective state in newly diagnosed malignant melanoma patients.

The primary purpose of this study was to determine if a psychoeducational nursing intervention including (a) health education, (b) stress management, and (c) the teaching of coping skills could enhance the coping behavior and affective state of newly diagnosed Stage I/II malignant melanoma patients. The secondary purpose was to determine if this intervention could be implemented by a nurse and integrated into the overall patient care program. Sixty-one patients were randomized to a control condition or an experimental condition that received and educational manual plus 3 h of individual nurse teaching. Despite randomization, experimental patients had significantly higher baseline distress. By 3 months there was a complete reversal of the baseline trend in Profile of Mood States (POMS) total mood disturbance (TMD), suggesting that the experimental subjects were experiencing less distress over time. Between-group analysis of change scores found significant decreases in experimental subjects for POMS TMD, fatigue, and Brief Symptom Index (BSI) somatization. Within-group analysis found significant experimental decreases for BSI somatization, anxiety, grand total, General Severity Index, and Positive Symptom Distress Index as well as for POMS anxiety, fatigue, confusion, vigor, and TMD. No significant changes were found for controls. Experimental patients were using significantly fewer ineffective passive resignation coping strategies than controls at 3 months.

The Positive Appearance Center: an innovative concept in comprehensive psychosocial cancer care.

Every year, more than one million people are diagnosed with cancer in the United States. Many of the treatments for cancer cause temporary or permanent physical changes that, along with the diagnosis, may lead to altered body image and diminished self-esteem in patients with cancer. The Positive Appearance Center was developed to help male and female patients with cancer deal with the cosmetic side effects and comfort needs related to their diagnosis and treatment. The Positive Appearance Center is part of a larger psychosocial program located in a comprehensive cancer center and is open to the public. Feedback from patients has been positive. Patients have cited the products and services provided by the center as major factors helping them cope with the physical and emotional aspects of their cancer.

Critical review of psychosocial interventions in cancer care.

The need for a large variety of psychosocial interventions is enhanced as increasing numbers of patients with cancer have longer survival. This article reviews the four interventions used most commonly: (1) education, (2) behavioral training, (3) individual psychotherapy, and (4) group interventions. It examines the outcomes of each type of intervention. This comprehensive review of the intervention literature reveals the availability of a wide range of options for patients with cancer and their potential psychological and physical health benefits.

Malignant melanoma. Effects of an early structured psychiatric intervention, coping, and affective state on recurrence and survival 6 years later.

OBJECTIVES: We evaluated recurrence and survival for 68 patients with malignant melanoma who participated in a 6-week structured psychiatric group intervention 5 to 6 years earlier, shortly after their diagnosis and initial surgical treatment. We also explored the role of several factors as possible predictors of outcome. DESIGN: This was a randomized controlled experimental study. The Cox proportion hazards regression model was used to quantify the relationship between treatment and the outcomes adjusted by the covariates (age, sex, Breslow depth, tumor site, baseline Profile of Mood States Total Mood Disturbance, baseline active-behavioral coping, baseline natural killer cell activity, and treatment [ie, group intervention]). The stepwise procedure was used for covariate selection. RESULTS: For control patients, there was a trend for recurrence (13/34) and a statistically significant greater rate of death (10/34) than for experimental patients (7/34 and 3/34, respectively). We found that being male and having a greater Breslow depth predicted greater recurrence and poorer survival. Analysis of multiple covariates found that only Breslow depth and treatment (ie, group intervention) were significant. Adjusting for Breslow depth, treatment effect remained significant. Finally, baseline affective distress and baseline coping were significant psychobehavioral predictors for recurrence and survival. Surprisingly, higher levels of baseline distress as well as baseline coping and enhancement of active-behavioral coping over time were predictive of lower rates of recurrence and death. CONCLUSION: Psychiatric interventions that enhance effective coping and reduce affective distress appear to have beneficial effects on survival but are not proposed as an alternative or independent treatment for cancer or any other illness or disease. However, the exact nature of this relationship warrants further investigation.

A structured psychiatric intervention for cancer patients. II. Changes over time in immunological measures.

We evaluated the immediate and long-term effects on immune function measures of a 6-week structure psychiatric group intervention for patients with malignant melanoma. Along with a reduction in levels of psychological distress and greater use of active coping methods, the following immune changes were seen at the 6-month assessment point in the intervention-group patients (n = 35) compared with controls (n = 26): significant increases in the percent of large granular lymphocytes (defined as CD57 with Leu-7) and natural killer (NK) cells (defined as CD16 with Leu-11 and CD56 with NKH1) along with indications of increase in NK cytotoxic activity; and a small decrease in the percent of CD4 (helper/inducer) T cells. At the 6-week follow-up point, the majority of these changes were not yet observable. The results indicate that a short-term psychiatric group intervention in patients with malignant melanoma with a good prognosis was associated with longer-term changes in affective state, coping, and the NK lymphoid cell system. Affective rather than coping measures showed some significant correlations with immune cell changes.