Quantifying Distances Between Non-Elliptical Clusters to Enhance the Identification of Meaningful Emotional Reactivity Subtypes.

Coordinated emotional responses across psychophysiological and subjective indices is a cornerstone of adaptive emotional functioning. Using clustering to identify cross-diagnostic subgroups with similar emotion response profiles may suggest novel underlying mechanisms and treatments.However, many psychophysiological measures are non-normal even in homogenous samples, and over-reliance on traditional elliptical clustering approaches may inhibit the identification of meaningful subgroups. Finite mixture models that allow for non-elliptical cluster distributions is an emerging methodological field that may overcome this hurdle. Furthermore, succinctly quantifying pairwise cluster separation could enhance the clinical utility of the clustering solutions. However, a comprehensive examination of distance measures in the context of elliptical and non-elliptical model-based clustering is needed to provide practical guidance on the computation, benefits, and disadvantages of existing measures. We summarize several measures that can quantify the multivariate distance between two clusters and suggest practical computational tools. Through a simulation study, we evaluate the measures across three scenarios that allow for clusters to differ in location, scale, skewness, and rotation. We then demonstrate our approaches using psychophysiological and subjective responses to emotional imagery captured through the Transdiagnostic Anxiety Study. Finally, we synthesize findings to provide guidance on how to use distance measures in clustering applications.

Clinical features and outcome of functional thyroid tumours in 70 dogs.

OBJECTIVE: To describe the clinical features and outcome of functional thyroid tumours in dogs. MATERIALS AND METHODS: Retrospective multi-institutional study of 70 dogs diagnosed with thyroid mass and concurrent hyperthyroidism. Clinical data regarding presentation, treatment, outcome and functional thyroid status were retrieved. RESULTS: Overall median survival of dogs with functional thyroid tumours was 35.1 months and 1- and 3-year survival rates were 83 and 49%, respectively. Median survival time was 72.6 months for dogs treated with surgical excision and 15.7 months for dogs that did not receive surgery. Of the 50 dogs treated by surgery and for which thyroid status was known following treatment, 64% developed hypothyroidism after surgery. Histopathologically confirmed metastasis was identified in 3% of dogs. CLINICAL SIGNIFICANCE: Dogs with functional thyroid tumours may survive a long time after surgical excision, although post-operative hypothyroidism is common.

Pyloric outflow obstruction secondary to sclerosing encapsulating peritonitis in a dog.

A 6-year-old, male neutered mixed breed dog was presented emergently with a three-week history of hyporexia, vomiting, diarrhoea and weight loss. Upon examination, the patient was dull, had generalised muscle atrophy, moderate abdominal pain and a mild amount of peritoneal effusion. A fluid-filled, distended, corrugated small bowel with marked gastroparesis and moderate peritoneal effusion was noted on abdominal ultrasonography. Endoscopy revealed hyperaemic and friable mucosa and a subjectively narrowed pylorus. Emergency exploratory celiotomy was performed due to worsening patient condition and revealed thick, diffuse, fibrous adhesions of the abdominal cavity. Based on these findings, sclerosing encapsulating peritonitis (SEP) was suspected. A large mass of omentum adjacent to the greater curvature of the stomach had caused a pyloric outflow obstruction. Adhesiolysis was attempted but was unsuccessful due to the friability of the small intestines. The dog was humanely euthanased under anaesthesia. A diagnosis of SEP was confirmed via necropsy. No underlying cause was identified. This is the first known case of a pyloric outflow obstruction secondary to SEP in a dog. Although rare, this condition should be considered as a differential for dogs with signs of a pyloric outflow obstruction with concurrent ascites and abdominal pain, hyporexia, vomiting and diarrhoea.

Heightened sleep propensity: a novel and high-risk sleep health phenotype in older adults.

OBJECTIVES: To reveal sleep health phenotypes in older adults and examine their associations with time to 5-year all-cause and cardiovascular mortality. DESIGN: Prospective longitudinal cohorts. SETTING: The Study of Osteoporotic Fractures and Outcomes of Sleep Disorders in Older Men Study. PARTICIPANTS: N = 1722 men and women aged ≥65 years matched 1:1 on sociodemographic and clinical measures. MEASUREMENTS: Self-reported habitual sleep health characteristics (satisfaction, daytime sleepiness, timing, efficiency, and duration) measured at an initial visit and longitudinal follow-up for mortality. RESULTS: Latent class analysis revealed 3 sleep health phenotypes: (1) heightened sleep propensity (HSP; medium to long duration, high sleepiness, high efficiency/satisfaction; n = 322), (2) average sleep (AS; medium duration, average efficiency, high satisfaction, low sleepiness; n = 1,109), and (3) insomnia with short sleep (ISS; short to medium duration, low efficiency/satisfaction, moderate sleepiness; n = 291). Phenotype predicted time to all-cause mortality (χ2 = 9.4, P = .01), with HSP conferring greater risk than AS (hazard ratio [95% confidence interval] = 1.48 [1.15-1.92]) or ISS (1.52 [1.07-2.17]), despite ISS reporting the poorest mental and physical health. Although sex did not formally moderate the relationship between phenotype and mortality, subgroup analyses indicated that these findings were driven primarily by women. Phenotype did not predict cardiovascular mortality. CONCLUSIONS: These analyses support the utility of examining multidimensional sleep health profiles by suggesting that the combination of long sleep, high efficiency/satisfaction, and daytime sleepiness-previously identified as independent risk factors-may be components of a single high-risk sleep phenotype, HSP. Further investigation of sex differences and the mechanisms underlying mortality risk associated with HSP is warranted.

The association between meal timing and frequency with cardiometabolic profile in patients with bipolar disorder.

OBJECTIVE: The goal of this study was to explore the association of timing of and frequency of meals with markers of cardiometabolic risk in patients with bipolar disorder in out-patient maintenance treatment. METHODS: We used Pittsburgh Sleep Diary and actigraphy measures for individuals with bipolar I disorder. Linear and logistic regression analyses were used to determine whether dinnertime, instability of dinnertime, and/or interval between meals were associated with metabolic syndrome and its components. RESULTS: Later dinnertime was associated with greater waist circumference (ß = 0.25, P = 0.02) after adjusting for age, sex, dinner-to-bed interval, and sleep duration. Longer breakfast-to-lunch intervals were also associated with greater waist circumferences (ß =-.35, P = .002) after adjusting for age, sex, and sleep duration. Neither instability of dinnertime nor number of meals per day was associated with the metabolic syndrome or its components. CONCLUSION: Weight gain is often perceived as inevitable side-effect of medications. While patients often need to be on medication to function, a more careful lifestyle assessment with attention to social rhythms and timing of activities may be critical not only for mood stability, but also to reduce cardiovascular risk.

Time-dependent tree-structured survival analysis with unbiased variable selection through permutation tests.

Incorporating time-dependent covariates into tree-structured survival analysis (TSSA) may result in more accurate prognostic models than if only baseline values are used. Available time-dependent TSSA methods exhaustively test every binary split on every covariate; however, this approach may result in selection bias toward covariates with more observed values. We present a method that uses unbiased significance levels from newly proposed permutation tests to select the time-dependent or baseline covariate with the strongest relationship with the survival outcome. The specific splitting value is identified using only the selected covariate. Simulation results show that the proposed time-dependent TSSA method produces tree models of equal or greater accuracy as compared to baseline TSSA models, even with high censoring rates and large within-subject variability in the time-dependent covariate. To illustrate, the proposed method is applied to data from a cohort of bipolar youths to identify subgroups at risk for self-injurious behavior.

Sleep duration is associated with dyslipidemia in patients with bipolar disorder in clinical remission.

BACKGROUND: The pathways to increased cardiovascular risk in bipolar disorder include health behaviors, psychosocial stress and long-term medication exposure. However, the evidence that the association between cardiovascular risk factors and bipolar disorder remains significant after controlling for these co-factors suggests that additional important risk factors have yet to be identified. Our hypothesis is that disturbances in the sleep-wake cycle are an important and under-recognized pathway through which affective disorders lead to increased cardiovascular risk. METHODS: In patients with bipolar disorder type 1 in clinical remission, we: 1) explored whether sleep disturbance predicted the endorsement of NCEP ATP-III criteria for dyslipidemia, independent of other lifestyle factors and 2) tested the association between low HDL (NCEP-ATP III) and sleep duration measured with actigraphy over an eight-day period. RESULTS: Median sleep duration is significantly associated with low HDL. The risk of having low HDL increases by 1.23 with every 30 minutes of reduced sleep time. LIMITATIONS: Since sleep patterns in patients with bipolar disorder are variable and irregular, it is possible that other sleep characteristics, not present during the span of our study, or the variability itself may be what drives the increased cardiovascular risk. CONCLUSIONS: Sleep characteristics of patients with bipolar disorder in clinical remission are associated with cardiovascular risk. More specifically, sleep duration was associated with low HDL. Clinicians should pay special attention to sleep hygiene in treating individuals with bipolar disorder, even when they are in clinical remission.

Pseudoepitheliomatous hyperplasia secondary to cutaneous aspergillus.

Cutaneous aspergillosis commonly occurs in immunocompromised hosts and may also complicate burn wounds. Pseudoepitheliomatous hyperplasia (PH) is a histologic reaction secondary to a wide range of stimuli, including fungal infection. We describe a case of an 18-year-old man, status-post burns over 70% of his total body surface area, with cutaneous aspergillosis of the axilla and secondary PH. A single case of PH secondary to primary aspergillosis has been described in the larynx but, to our knowledge, has never been described cutaneously. Histologic examination of the lesion reveals an irregularly acanthotic epidermis with deep invaginations within the dermis. There is an intense inflammatory reaction within the superficial and deep dermis. Numerous fungal forms are identified within the dermis. Special stains demonstrate septate hyphae with dichotomous branching, which is morphologically consistent with Aspergillus. Therefore, we conclude that cutaneous aspergillosis should be included in the differential diagnosis of causes of PH, especially in a patient population at risk for this infection.

Myofibroblast induction with transforming growth factor-beta1 and -beta3 in cutaneous fetal excisional wounds.

BACKGROUND/PURPOSE: In a noncontractile fetal rabbit model, the authors recently have shown the induction of excisional wound contraction with sustained-release cellulose implants formulated with transforming growth factor (TGF)-beta. The purpose of this study was to test the hypothesis that the excisional wound contraction in this model is associated with the induction of myofibroblasts in the surrounding dermis, demonstrated by the presence of alpha-smooth muscle actin. METHODS: Cellulose discs were formulated with either 1.0 microg of TGF-beta1 (n = 6); 1.0 microg of TGF-beta3 (n = 9); 10 microg of TGF-beta3 (n = 6); or their carrier protein, bovine serum albumin (BSA; n = 9), for sustained-release over 5 days. Each disc was implanted into a subcutaneous pocket on the back of a fetal New Zealand White rabbit in utero on day 24 of gestation (term, 31 days). A full-thickness, 3-mm excisional wound (7.4 mm2) was then made next to the implanted cellulose disc. All fetuses were harvested at 3 days. The amount of alpha-smooth muscle (SM) actin in the dermis around the implants and wounds was determined using immunohistochemical techniques. RESULTS: Excisional wounds exposed to 1.0 microg of TGF-beta1 (5.6+/-2.0 mm2), 1.0 microg of TGF-beta3 (6.9+/-1.0 mm2), and 10 microg of TGF-beta3 (2.7+/-1.0 mm2) were significantly smaller when compared with the BSA control group (12.8+/-1.1 mm2; P<.05). Furthermore, there was a significant increase in staining for alpha-SM actin in the TGF-beta1 (1.8+/-0.5) and 10 microg TGF-beta3 (2.8+/-0.2) groups in comparison with the scant staining in the BSA control group (0.5+/-0.2; P<.05). CONCLUSIONS: TGF-beta1 and -beta3 induce alpha-SM actin and contraction of cutaneous excisional wounds in a fetal noncontractile model. This model of inducible cutaneous excisional wound contraction may be useful in further determining the role of the myofibroblast in wound contraction and the physiology underlying this poorly understood aspect of wound healing.

Subcutaneous nodules caused by Pseudomonas aeruginosa without sepsis.

Pseudomonas aeruginosa infection can cause a wide array of skin manifestations. While some infections are mild, as are the cases with hot tub folliculitis and toe web or nail infection, others are a result of sepsis and can be fatal without prompt treatment. The classic skin finding of P. aeruginosa sepsis is Ecthyma gangrenosum, but other signs such as papules, petechiae, and hemorrhagic bullae can also be seen. Suppurative panniculitis can also be caused by P. aeruginosa sepsis and clinically manifests as solitary or multiple subcutaneous nodules. Reports in the literature describe these nodules in the setting of clinical sepsis or with positive blood cultures. We report a case of localized subcutaneous nodules on the leg caused by P. aeruginosa in a patient without sepsis or positive blood cultures. The source of the infection was thought to be from a traumatic inoculation. This raises the possibility that P. aeruginosa can cause subcutaneous nodules from a localized infection, perhaps via lymphangitic spread without the manifestations of sepsis.

Numbers and differentiation status of melanocytes in idiopathic guttate hypomelanosis.

The etiology and pathogenesis of idiopathic guttate hypomelanosis (IGH) are largely unknown. To investigate whether the pathologic alteration in IGH involves changes in melanocytic differentiation, cell number, or both, we studied nine lesions of IGH by immunoperoxidase, using monoclonal antibodies against the KIT receptor and a panel of melanocyte differentiation antigens (tyrosinase-related protein-1, tyrosinase, and gp100/pme117). In each case, compared with grossly normal non-lesional skin, IGH lesions showed markedly reduced numbers both of KIT+ cells and of cells expressing melanocyte differentiation antigens (p < 0.0001). Double immunofluorescence labeling of lesions revealed only scattered cells with a less-differentiated phenotype, i.e. cells positive for KIT but having low or undetectable TRP-1. These results indicate that the pathogenesis of IGH involves an absolute decrease in the number of melanocytes; a block in melanocyte differentiation does not appear to be a major component of the process.

Estrogen and progesterone receptors in androgenic alopecia versus alopecia areata.

In some situations, hair growth is under hormonal control. Androgenic alopecia is characterized as hormonally driven hair loss in the genetically susceptible individual. During pregnancy, hair growth is increased, as estrogen appears to prolong the anagen phase. However, postpartum hair loss is common, and thus may be related to a decrease in estrogen and or progesterone levels. In contrast, alopecia areata is not considered to be under hormonal control. We compared the immunohistochemical staining characteristics of nine cases of androgenic alopecia with those of 13 cases of alopecia areata using estrogen receptor (ER) and progesterone receptor (PR) markers. Estrogen receptor positivity in the dermal papilla was found in only two of 13 cases of alopecia areata, and in one case of androgenic alopecia. Six of 13 cases of alopecia areata demonstrated focal reactivity with the progesterone marker in a similar location, while only three cases of androgenic alopecia showed positivity with this antibody. Examination of the perifollicular fibroblasts for the ER marker showed positivity in one of 13 cases of alopecia areata and in one case of androgenic alopecia. Two cases of alopecia areata revealed focal staining in this location for the PR marker, while the androgenic alopecia cases failed to stain. These results indicate that estrogen and progesterone receptor expression is not significantly increased or decreased in the pilosebaceous units or surrounding mesenchymal cells in androgenic alopecia vs. alopecia areata. Therefore, an indirectly mediated process of estrogen/progesterone control on hair growth and development must be presumed for cases of androgenic alopecia.

Trichoepithelioma with an adjacent basal cell carcinoma, transformation or collision?

Trichoepitheliomas (TEs) are benign follicular neoplasms that can be difficult to separate histologically from basal cell carcinomas (BCCs). It is important to make this distinction, because the treatments and prognoses differ for the two lesions. Previous reports have employed both histologic and immunohistochemical data in order to separate these two lesions. It is believed that transformation from a TE to a BCC is a rare event. We describe a case in which a single lesion with features of TE and BCC is present in a patient with multiple lesions of BCC.

Squamous cell carcinoma of the gingiva with an atypical appearance.

An atypical presentation of squamous cell carcinoma of the mandibular gingiva is presented. This case, along with previously reported cases in the literature, demonstrate the need for thorough intraoral examination and investigation of any unexplained, persistent lesions. Emphasis is placed upon histopathologic examination of such lesions in order to arrive at a definitive diagnosis.

Differential sensitivity of estrogen/progesterone receptors and BRST-2 markers in metastatic ductal and lobular breast carcinoma to the skin.

Cutaneous metastases arising from breast carcinoma are quite common. A standard panel of immunohistochemical markers including estrogen receptor (ER), progesterone receptor (PR), and BRST-2 are frequently used in surgical pathology to identify neoplasms with breast differentiation. It is well known that as the grade of a tumor increases, and as tumors lose their differentiation, immunohistochemistry results become more unpredictable in determining possible primary sites of origin. Although previous studies have identified a decrease of ER sensitivity in breast metastases, a possible sensitivity differential of cutaneous metastases of invasive lobular versus invasive ductal carcinoma by using the standard immunohistochemical panel has not been previously reported. With the standard panel, we compared the staining sensitivity of metastatic invasive ductal carcinoma (10 cases) to metastatic invasive lobular carcinoma (four cases) to the skin. ER positivity was identified in one case of metastatic ductal carcinoma and none of the four lobular carcinomas. PR positivity was noted in all cases of metastatic ductal and lobular carcinoma. BRST-2 positivity was found in only two of 10 cases of metastatic ductal carcinoma and all four of four cases of metastatic lobular carcinoma. These results indicate that a differential sensitivity exists for the BRST-2 marker when comparing cutaneous metastases of invasive lobular with invasive ductal carcinoma.

Immunohistochemistry in diagnostic dermatopathology.

Immunopathology continues to be important in diagnostic dermatopathology. Immunopathology is an invaluable tool for assessing the tissue of origin or direction of differentiation of cells. In some cases this can result in a more precise diagnosis. This article reviews the role of immunopathology in determining the biologic behavior of hematolymphoid infiltrates. It explores the methodology of immunoperoxidase, discusses the most commonly used antibody reagents, and presents a series of diagnostic dilemmas in which immunopathology can be useful. In each case a strategy is established that maximizes the likelihood of making a definitive diagnosis.

Estrogen and progesterone receptors and anti-gross cystic disease fluid protein 15 (BRST-2) fail to distinguish metastatic breast carcinoma from eccrine neoplasms.

Cutaneous metastases of breast carcinoma can be histologically similar to primary skin tumors with eccrine differentiation. We compared the immunohistochemical staining characteristics of 15 metastatic breast carcinoma skin lesions in 12 patients to those of a series of primary eccrine tumors using estrogen receptor, progesterone receptor, and anti-gross cystic disease fluid protein-15 markers. Anti-gross cystic disease fluid protein-15 positivity was noted in 7 of 15 breast carcinoma skin metastases, 0 of 5 benign eccrine tumors, 1 of 6 microcystic adnexal carcinomas, and 1 of 1 metastatic sweat gland adenocarcinoma. Estrogen receptor positivity was found in 1 of 15 metastatic breast carcinoma skin lesions, 0 of 5 benign eccrine tumors, 2 of 8 microcystic adnexal carcinomas, and 1 of 1 metastatic sweat gland adenocarcinoma. Progesterone receptor positivity was identified in 15 of 15 metastatic breast carcinoma skin lesions, 2 of 5 benign eccrine tumors, 5 of 8 microcystic adnexal carcinomas, and 1 of 1 metastatic sweat gland adenocarcinomas. These results indicate that standard immunohistochemical staining for estrogen receptors, progesterone receptors, and gross cystic fluid protein-15 markers will not reliably distinguish primary (or metastatic) eccrine tumors from cutaneous metastases of breast carcinoma.

Progesterone receptor positivity supports hormonal control of syringomas.

Syringomas may be at least partially under estrogen and/or progesterone influence, as they are more common in women and are known to proliferate at puberty. During pregnancy and the premenstrual period an increase in tumor size has also been described. We examined nine syringomas using immunohistochemical markers for estrogen (ER) and progesterone (PR) receptors. Scattered tumor cells displaying nuclear and cytoplasmic staining for ER were noted in one of the nine cases. Intense nuclear and cytoplasmic staining for PR was noted in most (> 80%) of the neoplastic cells in 8/9 syringoma cases. Current immunohistochemical evidence supports the theory that syringomas are under hormonal control.