Severe Food Protein-Induced Enterocolitis Syndrome After Hematopoietic Stem Cell Transplantation: Pediatric Case Report.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. In the last few years, after the publication of the consensus guidelines, with refined diagnostic criteria and improved awareness, FPIES is diagnosed with increased frequency. However, despite having a background of immune dysregulation, this complication has just been described once in the posttransplant setting, in an adult patient. To the best of our knowledge, there are no reports of pediatric patients developing FPIES after a hematopoietic stem cell transplant (HCT). METHODS: Retrospective review of a pediatric patient who developed severe FPIEs after a HCT. RESULTS: In this case report, the clinical presentation and diagnosis challenges of a pediatric patient who developed severe FPIES after HCT are described. The patient developed severe vomiting, diarrhea, lethargy, and shock and required admission to the pediatric intensive care unit in three occasions before the diagnosis was made. CONCLUSIONS: To the best of our knowledge, this is the first report of severe FPIES post-HCT in a pediatric patient. Physicians who are looking after pediatric patients in the post-HCT setting need to be aware of this possibility and include this entity in the differential diagnosis in order to reduce its associated morbidity.

Effects of RF Electric Currents on Hair Follicle Growth and Differentiation: A Possible Treatment for Alopecia.

Androgenic alopecia (AGA) is the most common type of alopecia and its treatments involve drugs that have various adverse effects and are not completely effective. Radiofrequency-based therapies (RF) are an alternative for AGA treatment. Although there is increasing clinical evidence of the effectiveness of RF for alopecia, its effects at the tissue and cellular level have not been studied in detail. The objective of this study was to analyze ex vivo the potential effect of RF currents used in capacitive resistive electrical transfer (CRET) therapy on AGA. Hair follicles (HFs) were donated by patients with AGA and treated with CRET. AGA-HFs were exposed in vitro to intermittent 448 kHz electric current in subthermal conditions. Cell proliferation (Ki67), apoptosis (TUNEL assay), differentiation (ß-catenin), integrity (collagen and MMP9), thickness of the epidermis surrounding HF, proportion of bulge cells and melanoblasts in AGA-HF were analyzed by immunohistochemistry. CRET increased proliferation and decreased death of different populations of AGA-HF cells. In addition, the melanoblasts increased in bulge and the epidermis surrounding the hair follicle thickened. These results support the effectiveness of RF-based therapies for the treatment of alopecia. However, clinical trials are necessary to know the true effectiveness of CRET therapy and other RF therapies for AGA treatment.

Radiofrequency Currents Modulate Inflammatory Processes in Keratinocytes.

Keratinocytes play an essential role in the inflammatory phase of wound regeneration. In addition to migrating and proliferating for tissue regeneration, they produce a large amount of cytokines that modulate the inflammatory process. Previous studies have shown that subthermal treatment with radiofrequency (RF) currents used in capacitive resistive electric transfer (CRET) therapy promotes the proliferation of HaCat keratinocytes and modulates their cytokine production. Although physical therapies have been shown to have anti-inflammatory effects in a variety of experimental models and in patients, knowledge of the biological basis of these effects is still limited. The aim of this study was to investigate the effect of CRET on keratinocyte proliferation, cytokine production (IL-8, MCP-1, RANTES, IL-6, IL-11), TNF-α secretion, and the expression of MMP9, MMP1, NF-κB, ERK1/2, and EGFR. Human keratinocytes (HaCat) were treated with an intermittent 448 kHz electric current (CRET signal) in subthermal conditions and for different periods of time. Cell proliferation was analyzed by XTT assay, cytokine and TNF-α production by ELISA, NF-κB expression and activation by immunofluorescence, and MMP9, MMP1, ERK1/2, and EGF receptor expression and activation by immunoblot. Compared to a control, CRET increases keratinocyte proliferation, increases the transient release of MCP-1, TNF-α, and IL-6 while decreasing IL-8. In addition, it modifies the expression of MMPs and activates EGFR, NF-κB, and ERK1/2 proteins. Our results indicate that CRET reasonably modifies cytokine production through the EGF receptor and the ERK1/2/NF-κB pathway, ultimately modulating the inflammatory response of human keratinocytes.

Anti-Fibrotic Effects of RF Electric Currents.

Hypertrophic scars and keloids are two different manifestations of excessive dermal fibrosis and are caused by an alteration in the normal wound-healing process. Treatment with radiofrequency (RF)-based therapies has proven to be useful in reducing hypertrophic scars. In this study, the effect of one of these radiofrequency therapies, Capacitive Resistive Electrical Transfer Therapy (CRET) on biomarkers of skin fibrosis was investigated. For this, in cultures of human myofibroblasts treated with CRET therapy or sham-treated, proliferation (XTT Assay), apoptosis (TUNEL Assay), and cell migration (Wound Closure Assay) were analyzed. Furthermore, in these cultures the expression and/or localization of extracellular matrix proteins such as α-SMA, Col I, Col III (immunofluorescence), metalloproteinases MMP1 and MMP9, MAP kinase ERK1/2, and the transcription factor NFκB were also investigated (immunoblot). The results have revealed that CRET decreases the expression of extracellular matrix proteins, modifies the expression of the metalloproteinase MMP9, and reduces the activation of NFκB with respect to controls, suggesting that this therapy could be useful for the treatment of fibrotic pathologies.

Can we predict an incomplete capsule endoscopy? Results of a multivariate analysis using a logistic regression model.

BACKGROUND AND AIMS: small bowel capsule endoscopy (SBCE) does not reach the cecum within the battery lifetime in approximately 15-35 % of patients. Incomplete examinations result in diagnostic delays and increase the economic burden. To date, risk factors for incomplete examinations have been described with contradictory results. The aims of this study were to analyze the rate and identify risk factors for incomplete examinations, excluding capsule retentions, in a large cohort of patients. METHODS: data from 1,894 consecutive SBCE examinations performed from January 2009 to December 2015 were analyzed. Variables recorded included demographics, past medical and surgical history, biochemical parameters and procedure characteristics. The rate of incomplete examinations, excluding capsule retentions, was calculated and a multivariate analysis using a logistic regression model was performed in order to evaluate predictive factors. RESULTS: the incidence of incomplete examinations, excluding capsule retentions, was 10.1 % (187 incomplete procedures). The multivariate analysis showed that age > 65 years, gastric transit time > 41 minutes and SB transit time > 286 minutes are predictive factors for incomplete examinations, increasing the probability of this event by 199 % (OR: 1.99; 95 % CI: 1.34-2.95), 260 % (OR: 2.60; 95 % CI: 1.72-3.93) and 352 % (OR: 3.52; 95 % CI: 2.26-5.48), respectively. CONCLUSIONS: age > 65 years, gastric transit time > 41 minutes and SB transit time > 286 minutes are predictive factors for incomplete examinations excluding capsule retentions. Both age and gastric transit time events are known before the procedure ends. Therefore, pharmacologic or endoscopic measures may be taken into account to avoid incomplete examinations.

Outcomes of peroral endoscopic myotomy in patients with spastic esophageal motility disorders that do not fulfill Chicago Classification criteria.

INTRODUCTION: per-oral endoscopic myotomy (POEM) has become a mainstream treatment for achalasia and is a promising therapy in spastic disorders. METHODS: this is a retrospective study of prospectively collected data (case series). We present the first results of the use of POEM in patients with atypical spastic esophageal motor disorders that do not satisfy current Chicago Classification criteria. Seven consecutive patients with troublesome and persistent symptoms (12-180 months) related to atypical spastic esophageal motor dysfunction were systematically assessed before and after POEM, the extent of which was tailored by manometric findings. In five of the patients, other endoscopic or surgical procedures had failed. RESULTS: high-resolution manometry (HRM) showed a spastic esophageal body contractile segment in varying positions and lengths along the esophageal body which did not meet Chicago Classification criteria. After POEM, dysphagia and/or chest pain had either resolved or was greatly reduced. HRM 3-6 months after myotomy showed that the regions of spastic contraction targeted by myotomy had been ablated. There were no major complications. The clinical responses were fully maintained up to the most recent assessments after POEM (range 7-44 months). CONCLUSION: in our seven patients, POEM was a highly effective treatment for patients with troublesome symptoms related to atypical spastic esophageal motility disorders.

In vitro stimulation with radiofrequency currents promotes proliferation and migration in human keratinocytes and fibroblasts.

Capacitive-resistive electric transfer (CRET) therapies have been proposed as strategies for regeneration of cutaneous tissue lesions. Previous studies by our group have shown that intermittent stimulation with 448 kHz CRET currents at subthermal densities promotes in vitro proliferation of human stem cells involved in tissue regeneration. The present study investigates the effects of the in vitro exposure to these radiofrequency (RF) currents on the proliferation and migration of keratinocytes and fibroblasts, the main cell types involved in skin regeneration. The effects of the electric stimulation on cell proliferation and migration were studied through XTT and wound closure assays, respectively. The CRET effects on the expression and location of proteins involved in proliferation and migration were assessed by immunoblot and immunofluorescence. The obtained results reveal that electrostimulation promotes proliferation and/or migration in keratinocytes and fibroblasts. These effects would be mediated by changes observed in the expression and location of intercellular adhesion proteins such as ß-catenin and E-cadherin, of proteins involved in cell-to-substrate adhesion such as vinculin, p-FAK and the metalloproteinase MMP-9, and of other proteins that control both processes: MAP kinases p-p38, p-JUNK and p-ERK1/2. These responses could represent a mechanism underlying the promotion of normotrophic wound regeneration induced by CRET. Indeed, electric stimulation would favor completion of granulation tissue formation prior to the closure of the outer tissue layers, thus preventing abnormal wound cicatrization or chronification.

Primary dermal pleomorphic liposarcoma: utility of adipophilin and MDM2/CDK4 immunostainings.

Liposarcoma, usually arises in deep soft tissues and pleomorphic liposarcoma (PL), is the rarest histopathologic variant. However, 15 cases of entirely dermal PL have been reported. We describe a case of a 79-year-old man who developed a rapidly growing nodule on his thorax. Excisional biopsy was performed and immunohistochemical studies were carried. The lesion was a well-circumscribed dermal nodule composed of multivacuolated pleomorphic lipoblasts and atypical mitotic figures. Neoplastic cells expressed CD10 and resulted negative S100 protein, Melan-A, MITF-1, AE1/AE3, CD4, CD68 (PGM1), retinoblastoma gene family protein, pericentrine and lysozyme. Adipophilin stain showed the lipid contents in the cytoplasm of the neoplastic cells. MDM2 and CDK4 resulted both negative. A diagnosis of primary dermal PL was made. This case shows the utility of adipophilin immunostaining to prove the lipid contents in neoplastic cells, which has the advantage of using formalin-fixed paraffin-embedded tissue and making needless frozen sections and ultrastructural studies to show these findings. Negative MDM2/CDK4 staining in our case argues against the possibility of dedifferentiated liposarcoma and further supports the diagnosis of true PL.

Metformin-Induced Generalized Fixed Drug Eruption With Cutaneous Hemophagocytosis.

Fixed drug eruption (FDE) consists of recurrent dusky-red to brownish macules or patches at the same sites after the readministration of the causative drug. It usually presents as a solitary lesion, but generalized eruptions have been described. The most frequently implied drugs are antibiotics, anticonvulsants, and analgesics. Only 2 cases due to metformin have been reported. Histopathologic features of FDE include vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphocytic infiltrate. Cutaneous hemophagocytosis in the context of a FDE has not been previously reported. We describe the case of an 86-year-old man who developed a pruritic generalized macular eruption of reddish to violaceous patches. Skin biopsy was performed and the dermal infiltrate was immunohistochemically studied. Histopathology showed interface dermatitis with vacuolar degeneration of the basal layer, necrotic keratinocytes, and superficial and deep perivascular lymphohistiocytic infiltrate. In deep dermis, histiocytes with engulfed cells inside their cytoplasm were seen. Lymphoid enhancer binding factor 1 immunostain demonstrated that most of these cells were lymphocytes. We present the first case with cutaneous hemophagocytosis in the context of a metformin-induced generalized FDE. In this particular case, hemophagocytosis was just a histopathologic finding with no systemic consequences for the patient.

Anti-NXP2-Positive Paraneoplastic Dermatomyositis With Histopathologic Changes Confined to the Acrosyringia.

BACKGROUND: Paraneoplastic syndromes consist of a group of disorders that are not related to the extension of the primary tumor or its metastases and that might be the first manifestation of a hidden neoplasm. It is a well-known association between dermatomyositis (DM) and cancer, especially gynecological tumors in women and lung cancer in men. METHODS: We describe the case of a 67-year-old male who developed muscular weakness and pruritic skin lesions. Skin biopsies were performed and histologic findings were consistent with DM. RESULTS: Skin biopsy showed interface dermatitis with vacuolar degeneration of the basal layer, dermal mucin deposits, and necrotic keratinocytes in the acrosyringia, a finding that has been previously reported in lupus erythematous but not in DM. Autoimmunity tests showed positivity for antinuclear antibodies and anti-NXP2, a recently described antibody associated with juvenile DM and, more rarely, with paraneoplastic DM. CONCLUSION: We present the first case in the literature with histopathologic changes of DM affecting the acrosyringia. Besides, our patient autoimmunity results support the utility of the new myositis-specific autoantibodies and its relation with a clinical phenotype.

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.

BACKGROUND: It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS: At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS: A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS: Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Electric currents of 448 kHz upregulate anti-senescence pathways in human dermal fibroblasts.

BACKGROUND: Currently, finding new therapeutic strategies that reduce skin aging is a challenge for dermatologists and aesthetic doctors. In recent years, physical therapies have been included in the options for antiaging treatments; however, the biological bases of such treatments have scarcely been studied. One of these physical therapies is capacitive-resistive electric transfer (CRET) therapy. Previous studies have shown that subthermal treatment with CRET promotes the proliferation and migration of various cell types involved in skin regeneration, such as human ADSC (stem cells), fibroblasts, or keratinocytes. OBJECTIVE: This study investigates the effects of in vitro treatment with CRET-Std (standard, non-modulated signal) or CRET-Mod (modulated signal) on cell proliferation and migration, markers of aging, and extracellular matrix production. METHODS: Three types of human dermal fibroblasts were used: neonatal fibroblasts (HFn), replicative senescent fibroblasts (HFs), and adult fibroblasts (HFa). The effects of electric stimulation on cell proliferation and migration were studied through XTT and wound closure assays, respectively. The expression of the aging marker ß-galactosidase was assessed using a colorimetric assay, whereas immunoblot, immunofluorescence, and ELISAs were carried out to analyze the expression levels of migration, aging, and extracellular matrix proteins. RESULTS: The treatment with CRET-Std increased HFn and HFa proliferation, as well as migration in the three types of fibroblasts studied compared to those of the controls. Conversely, CRET-Mod did not modify either of these two processes with respect to the controls. Additionally, CRET-Std also reduced the cellular senescence markers ß-gal, vimentin, p53, and p21 in all three types of human skin fibroblasts. In addition, the application of CRET-Std also induced fibronectin production in HFn and was able to stimulate ECM neocollagenesis. CONCLUSION: CRET treatment improves a number of functions related to migration and proliferation, and it reduces age-related cellular changes in human dermal fibroblasts. Therefore, the use of this CRET therapy to reduce the signs of dermal aging and to promote tissue regeneration could be of interest.

Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24.

Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10(-34)), rs1867277A (p=5.90×10(-24)), rs944289T (p=6.95×10(-7)), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (P(GG vs GT + TT)=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10(-13)) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (∼11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).

Does capsule endoscopy impact clinical management in established Crohn's disease?

BACKGROUND: Capsule endoscopy (SBCE) has developed a relevant role in patients with established Crohn's Disease (CD). However, evaluation of the impact in clinical management has been scarce. AIMS: To evaluate therapeutic impact of SBCE in an 11-year real-life cohort of known CD patients. METHODS: Retrospective single center study including all patients with established CD submitted to SBCE procedure from 01/01/2008 to 31/12/2019. Patency capsule was used in selected patients. Small bowel mucosal inflammation was quantified using Lewis score. Therapeutic impact was defined as a change in CD-related treatment recommended based on SBCE results. Patients were assigned to four groups regarding SBCE indication: staging, flare, post-op and remission. RESULTS: From the 432 SBCE performed 87.5% were conclusive. Active disease was present in 63.7 of patients; 41.6% mild inflammation and 21.9% moderate-to-severe activity. A change of management was guided by SBCE in 51.3% of procedures: 199 (46.1%) escalation and 23 (5.3%) de-escalation, with significant changes in all groups. Escalation increased with disease activity: 57.8% in mild and 89.5% in moderate-to-severe disease. De-escalation was conducted in 13.9% procedures with mucosal healing and 1.1% with mild disease. CONCLUSION: SBCE is a useful tool for guiding therapeutic management in CD patients both for treatment escalation and de-escalation.

Response of human cancer cells to simultaneous treatment with sorafenib and radiofrequency current.

Due to their alleged analgesic, anti-inflammatory and tissue regenerative effects, capacitive-resistive electrothermal therapy (CRET), which is based on non-invasive exposure to radiofrequency (RF) currents, is often applied to chemotherapeutically treated patients with cancer. Our previous studies have demonstrated that subthermal CRET currents can elicit a number of cell responses, including anti-proliferative effects, in the human liver cancer cell line HepG2. Such effects involve significant changes in the regulation of proteins involved in MAPK signaling pathways, which are also implicated in the cancer cell response to standard anticancer drugs such as sorafenib. This overlap in response pathways may lead to competitive, neutralizing or blocking interactions between the electrical and chemical treatments, thus raising questions on the advisability of CRET treatment for their analgesic, anti-inflammatory or other purposes in patients undergoing chemotherapy. The present study analyzed the effects of simultaneous treatment with sorafenib and 448-kHz, subthermal CRET current on the proliferation and viability of HepG2 cell cultures. Cell viability was assessed through Trypan blue or XTT assays, while flow cytometry was applied for cell cycle and apoptosis analysis. The expression of proteins involved in cell proliferation were assessed by immunoblotting and immunofluorescence. The results revealed no evidence to suggest that the electrical treatment counteracted or neutralized the cellular response to sorafenib at the different conditions evaluated. Furthermore, at the standard pharmacological sorafenib concentration, 5 µM, the combined treatment elicited an anti-proliferative response significantly stronger than that induced by each of the treatments when applied separately in HepG2 cells. These data do not support the hypothesis that CRET exposure may inhibit or diminish the effects of a chemotherapeutic drug used in cancer treatment, and highlights the requirement for further investigation into the cell response to the combined action of electrical and chemical treatments.

Can we predict an incomplete capsule endoscopy? Results of a multivariate analysis using a logistic regression model

Background and aims: small bowel capsule endoscopy (SBCE) does not reach the cecum within the battery lifetime in approximately 15-35 % of patients. Incomplete examinations result in diagnostic delays and increase the economic burden. To date, risk factors for incomplete examinations have been described with contradictory results. The aims of this study were to analyze the rate and identify risk factors for incomplete examinations, excluding capsule retentions, in a large cohort of patients.Methods: data from 1,894 consecutive SBCE examinations performed from January 2009 to December 2015 were analyzed. Variables recorded included demographics, past medical and surgical history, biochemical parameters and procedure characteristics. The rate of incomplete examinations, excluding capsule retentions, was calculated and a multivariate analysis using a logistic regression model was performed in order to evaluate predictive factors.Results: the incidence of incomplete examinations, excluding capsule retentions, was 10.1 % (187 incomplete procedures). The multivariate analysis showed that age > 65 years, gastric transit time > 41 minutes and SB transit time > 286 minutes are predictive factors for incomplete examinations, increasing the probability of this event by 199 % (OR: 1.99; 95 % CI: 1.34-2.95), 260 % (OR: 2.60; 95 % CI: 1.72-3.93) and 352 % (OR: 3.52; 95 % CI: 2.26-5.48), respectively.Conclusions: age > 65 years, gastric transit time > 41 minutes and SB transit time > 286 minutes are predictive factors for incomplete examinations excluding capsule retentions. Both age and gastric transit time events are known before the procedure ends. Therefore, pharmacologic or endoscopic measures may be taken into account to avoid incomplete examinations. (AU)

The European Union Integrated Political Crisis Response Arrangements: Improving the European Union's Major Crisis Response Coordination Capacities.

In recent years, the European Union (EU) has progressively assumed more and more of a primary role in crisis response coordination. The EU Integrated Political Crisis Response arrangements (IPCR) were recently approved to facilitate this task. These new agreements, which substitute for the Crisis Coordination Agreements, will add more flexibility to crisis response mechanisms in the EU. They will also strengthen cooperation between the different relevant agents in a major crisis situation and create new useful tools, such as the Integrated Situational Awareness and Analysis. Their real performance still needs to be fully tested, but some weakness can already be foreseen. This article provides a deep analysis of this new legislation.

[Transsexuality: law and health-related aspects in the Spanish legal system]. / La transexualidad: aspectos jurídico-sanitarios en el ordenamiento español.

The social weight of transsexual groups has been and continues to be crucial in many aspects regarding transsexuality, from the progressive elimination of discrimination to influence in the legislative branch. This paper especially discusses a classic demand of these groups, comprehensive medical treatment of transsexual people within the National Health System. Thus, progress in the development of an adequate healthcare system for these groups, their treatment in the legal systems of Spain in general and of some of its autonomous communities with more noteworthy laws (especially in Andalusia, an autonomous community that has been pioneering in this regard, as well as the Basque Country and Navarre) and remaining challenges will be observed in this work. The article will also take particular note of the substantial developments that the publication of the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders has established in this area.