Search

Rationale: Given the large number of patients that does not respond sufficiently to currently available treatment for anxiety disorders, there is a need for improved treatment., Objectives: We evaluated the anxiolytic effects of corticotropin releasing factor (CRF) 1 receptor antagonists and glucocorticoid receptor (GR) antagonists in the separation-induced vocalization test in guinea pigs and transgenic mice with central CRF overexpression. Furthermore, we explored effects of these drugs when given in combination with a suboptimal dose of a selective serotonin re-uptake inhibitor (SSRI)., Methods: In guinea pig pups, the CRF 1 receptor antagonists CP-154,526 and DMP695, and the GR antagonists mifepristone and Org34517 (all at 2.5, 10 and 40mg/kg intraperitoneally (IP)) were tested alone or in combination with 0.63mg/kg paroxetine IP. In CRF overexpressing mouse pups and wild type littermates, effects of CP-154,526 (10, 20 and 40mg/kg subcutaneously (SC)) and mifepristone (5, 15, 45mg/kg SC) were studied alone or in combination with 0.03mg/kg paroxetine SC., Results: CRF 1 but not GR antagonists reduced the number of calls relative to vehicle in guinea pigs and mice, independent of genotype. Treatment of CRF 1 receptor or GR antagonists with paroxetine had no combined effect in guinea pigs, wild type or CRF overexpressing mice., Conclusions: Current results indicate robust anxiolytic properties of CRF 1 receptor antagonists in guinea pigs and mice overexpressing CRF, and lack thereof of GR antagonists. Although no combined treatment effects were observed, it would be interesting to study combined treatment of CRF 1 receptor antagonists with SSRIs following chronic drug administration., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Desmoplastic melanoma (DM) is an uncommon malignancy associated with a high local recurrence rate. The aim of this systematic review was to determine the positivity rate of sentinel lymph node biopsy (SLNB) in patients with DM. The secondary outcome was to establish if SLNB is warranted for both pure DM (PDM) and mixed DM (MDM)., Methods: A full systematic literature review of SLNB in DM was performed by two authors in January 2016. Ovid MEDLINE, Ovid EMBASE and the Cochrane Central Register of Controlled Trials were searched., Results: Sixteen studies involving 1519 patients having SLNB in DM were included, of which 99 patients had positive SLNB (6.5%). Two articles reported a significantly reduced disease-free survival (DFS) with positive SLNB and three published a reduced melanoma-specific survival (MSS). Six studies compared SLNB in MDM and PDM. Of the 275 patients, 38 (13.8%) had a positive SLNB in MDM compared to 17 of 313 patients (5.4%) with positive SLNB in PDM., Conclusions: Rates of positive SLNB in DM are reduced compared to other variants of melanoma; however, nodal status may still predict DFS and MSS. MDM is associated with a higher rate of micro-metastases to regional lymph nodes than PDM, and DFS and MSS may be lesser in MDM than in PDM. We would recommend the consideration of SLNB in MDM. However, with such low rates of positive SLNB in PDM, and in the absence of high-risk features to stratify patients, we would not recommend SLNB in PDM., (Copyright © 2016 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible after primary excision. To date, there is no evidence to support this timeframe., Aim: To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients., Methods: Between 1993 and 2008, 1080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors., Results: Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00 mm (IQR 1.90-4.80 mm), 442 (44%) were ulcerated. Median follow-up was 36 months (IQR 20-62 months). Median time interval was 47 days (IQR 32-63 days). Median Breslow thickness was equal for both <47 days and ≥47 days interval: 3.00 mm (1.90-5.00 mm) vs 3.00 mm (1.90-4.43 mm) (p = 0.402). Sentinel node tumor burden was significantly higher in patients operated ≥47 days (p = 0.005). Univariate survival was not significantly different for median time interval. Multivariable analysis confirmed that time interval was no independent prognostic factor for MSS., Conclusions: Time interval from primary melanoma excision until SNB was no prognostic factor for MSS in this SNB positive cohort. This information can be used to counsel patients., (Copyright © 2016 Elsevier Ltd and British Association of Surgical Oncology/European Society of Surgical Oncology. All rights reserved.)

Signaling between endothelial cells, endothelial progenitor cells, and stromal cells is crucial for the establishment and maintenance of vascular integrity and involves exosomes, among other signaling pathways. Exosomes are important mediators of intercellular communication in immune signaling, tumor survival, stress responses, and angiogenesis. The ability of exosomes to incorporate and transfer messenger RNAs (mRNAs) encoding for "acquired" proteins or micro RNAs (miRNAs) repressing "resident" mRNA translation suggests that they can influence the physiological behavior of recipient cells. We demonstrate that miR-214, an miRNA that controls endothelial cell function and angiogenesis, plays a dominant role in exosome-mediated signaling between endothelial cells. Endothelial cell-derived exosomes stimulated migration and angiogenesis in recipient cells, whereas exosomes from miR-214-depleted endothelial cells failed to stimulate these processes. Exosomes containing miR-214 repressed the expression of ataxia telangiectasia mutated in recipient cells, thereby preventing senescence and allowing blood vessel formation. Concordantly, specific reduction of miR-214 content in exosome-producing endothelial cells abolishes the angiogenesis stimulatory function of the resulting exosomes. Collectively, our data indicate that endothelial cells release miR-214-containing exosomes to stimulate angiogenesis through the silencing of ataxia telangiectasia mutated in neighboring target cells.

The burden on caregivers of patients with obsessive-compulsive disorder (OCD) is an important yet under-researched area in the Chinese population. This study aimed to assess the pattern and determinants of burden reported by caregivers of adults with OCD in Hong Kong. Seventy-seven OCD patient-caregiver dyads were recruited from a psychiatric out-patient clinic. Adults were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Global Assessment of Functioning (GAF) scale. Caregivers were interviewed with the Chinese version of the Family Burden Interview Schedule. Ninety-nine percent of the caregivers experienced objective burden. Mothers of patients with OCD experienced the greatest caregiver subjective burden. Multivariate analysis showed that GAF explained 41.5% and 49.8% of the variance of objective and subjective burden respectively. The functional level of OCD adults was an important determinant of both the objective and subjective burden on caregivers., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Exosomes are 40-100 nm membrane vesicles secreted into the extracellular space by numerous cell types. These structures can be isolated from body fluids including urine and plasma. Exosomes contain proteins, mRNAs, miRNAs, and signaling molecules that reflect the physiological state of their cells of origin and consequently provide a rich source of potential biomarker molecules. Aside from diagnostic uses, exosome-mediated transfer of proteins, mRNAs, miRNAs, and signaling molecules offer the promise that they may be used for therapeutic purposes. In this review, we integrate new knowledge about exosomes from outside the field of nephrology with recent progress by renal researchers in order to provide a basis for speculation about how the study of exosomes may affect the fields of nephrology and renal physiology in the next few years.

Botulinum toxin type A (BTX-A) has been used therapeutically for the treatment of spastic disorders for many years. More recently, the therapeutic utility of BTX-A in the treatment of hyperhidrosis has been recognised. While studies have reported on the efficacy of BTX-A in managing hyperhidrosis, long term data are required in order for the treatment implications to be fully appreciated. We report on a case of severe atrophy of the intrinsic muscles of the hands in a patient treated with intra-palmar BTX-A (Dysport, Speywood, UK) injections for hyperhidrosis. To our knowledge this has not been described in the literature before.

Interstitial deletions of 7q11.23 cause Williams-Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams-Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000-1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI. Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.

Over the past decades several epidemiological studies have been published reporting on incidence trends, hospital admissions, etiological factors and outcome of both acute and chronic pancreatitis. Over time, the incidence of acute pancreatitis has increased in the Western countries. Also, the number of hospital admissions for both acute and chronic pancreatitis have increased. These upward time trends possibly reflect a change in the prevalence of main etiological factors (e.g. gallstones and alcohol consumption) and cofactors such as obesity and genetic susceptibility. Acute and chronic pancreatitis are associated with significant morbidity and mortality and a substantial use of health care resources. Although the case-fatality rate of acute pancreatitis decreased over time, the overall population mortality did not change for both acute and chronic pancreatitis. This chapter will focus on recent developments in the epidemiology, aetiology, natural course and outcome of both acute and chronic pancreatitis.

To evaluate cell-mediated immunity in influenza-infected cotton rats, we compared the cellular composition of spleen, mediastinal lymph nodes (MLN) and bronchoalveolar lavage (BAL) after primary and secondary infection. There was an increase in cellularity in the MLN after primary infection that was further expanded upon rechallenge. CD4(+) T cells expanded after primary infection, but there was preferential increase in the number of CD4-negative T cells following secondary challenge. After primary infection, a large proportion of the monocytes and NK cells were present in the BAL while a T cell population dominated after secondary infection. CD4(+) T cells were predominant in this population unless the animals had been challenged with heterosubtypic influenza A virus. These studies are the first to show evidence of a memory T cell response to influenza infection in cotton rats and show quantitative and qualitative differences between the recall response to homosubtypic and heterosubtypic viruses.

Objective: Depressive disorders have been shown to be associated with cardiac diseases and death, but the underlying disease mechanism is unclear. The authors hypothesized that the cardiac morbidity and mortality after depression in late life is mediated by subclinical atherosclerosis and is thus confined to ischemic heart diseases., Method: Using the population-based cohort of the Longitudinal Aging Study Amsterdam, 2,403 men and women aged 55 and over without cardiac disease were followed to assess the onset of cardiac disease or cardiac death. Ischemic heart diseases (angina pectoris, [non]fatal myocardial infarction) were distinguished from other cardiac diseases (congestive heart failure, arrhythmia). Major depressive disorder (MDD) was defined according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) criteria. Subthreshold depression was defined as clinically relevant depressive symptoms not fulfilling DSM criteria., Results: After a mean follow up of 7.2 years, 444 first cardiac events occurred, of which 252 were primary ischemic events and 192 other cardiac events. Cox regression analysis adjusted for physical health variables showed that, when compared with nondepressed respondents, those with MDD had a relative risk (RR) of 2.09 (95% confidence interval: 1.13-3.85) for any cardiac event. Considering only ischemic events, the RR conferred by MDD increased to 3.00 (1.51-5.93), whereas the RR declined to 0.96 (0.24-3.89) for all other cardiac events. Subthreshold depression did not increase the risk of future cardiac events., Conclusion: Major depression in older age predicts first cardiac events. The excess cardiac morbidity and cardiac mortality after major depression could entirely be attributed to ischemic heart diseases.

Recent publications have suggested that sentinel lymph node biopsy (SLNB) and completion lymphadenectomy (CLND) increase the rate of local and in-transit disease up to 23% in sentinel node positive group of patients with cutaneous melanoma. This retrospective study combined the data from two national centres on local and in-transit disease in 972 melanoma patients who underwent SLNB procedure over 6.5 years period. In total, 77 patients (7.9%) developed loco-regional recurrence: 41 (4.2%) local recurrence only and 36 patients (3.7%) in-transit metastases during a mean follow-up of 42 months. Patients with positive sentinel lymph node were three times more likely to develop loco-regional metastases than those with no nodal disease (17 vs. 5.6%). Over one third of all recurrences developed following excision of thick (Breslow thickness over 4mm) primary tumours. In both centres age and Breslow thickness were found to be significantly higher in the recurrence group (p<0.001 for both). This study revealed a strong association between increased risk of loco-regional metastases and aggressive tumour biology and adverse patients factors. No conclusive evidence was found to support an increased incidence in patients undergoing SLNB and CLND compared to that published for patients undergoing wide local excision alone.

Sentinel lymph nodes provide an excellent opportunity to study early immune responses to cancer. However, harvesting live cells has not previously been possible, because it conflicts with the need to preserve tissue for histological interpretation. This study used scrape cytology on 26 sentinel and 8 non-sentinel nodes, harvested from 17 stage I/II melanoma patients undergoing sentinel node biopsy. Numbers of viable cells harvested before and after cryopreservation were measured and the effect on subsequent histology assessed. The mean number of cells harvested from 26 sentinel nodes was 7.06 x 10(6) (range 0.1-32.2), with a mean viability of 99.5% (range 87-100, lower 95% CI 98.5%). Furthermore, counts and viabilities were well maintained after cryopreservation. Flow cytometry confirmed CD3+, CD20+ and lineage-1-/HLA-DR+ subpopulations, consistent with T-lymphocytes, B-lymphocytes and dendritic cells, respectively. Importantly, there was no discernible change in histological detail and the proportion of positive sentinel nodes remained unchanged. This technique will allow more functional and quantitative approaches to sentinel lymph node research.

Sentinel node biopsy (SNB) is now widely used for accurate staging of patients with clinical stage I or II malignant melanoma. We describe the use of SNB in five patients with in-transit recurrence (stage IIIB) and demonstrate that it provides accurate staging of the lymph nodes in this group of patients.

It is generally felt that a halo naevus is benign, and patients can be reassured. The lesion is frequently left alone. We present a case where the clinician felt reassured, but at the patient's insistence the lesion was excised. The histology result was not anticipated.

Lymphoscintigraphy combined with sentinel lymph node biopsy has become a powerful and sensitive tool in establishing nodal spread in cutaneous melanoma, as well as in breast and other cancers. Although the technique is reliable and validated, there is, as yet, no proven clinical benefit. A suggested benefit of sentinel lymph node biopsy is that a negative biopsy may decrease the psychological morbidity associated with malignancy by reassuring the patient that he or she has localised disease. We studied a group of patients with cutaneous melanoma who underwent sentinel lymph node biopsy, and found that although they did gain some psychosocial benefit from the procedure, this was short term and they were still significantly concerned about their disease status., (Copyright 2002 The British Association of Plastic Surgeons.)