Critical insolation-CO2 relation for diagnosing past and future glacial inception.

The past rapid growth of Northern Hemisphere continental ice sheets, which terminated warm and stable climate periods, is generally attributed to reduced summer insolation in boreal latitudes. Yet such summer insolation is near to its minimum at present, and there are no signs of a new ice age. This challenges our understanding of the mechanisms driving glacial cycles and our ability to predict the next glacial inception. Here we propose a critical functional relationship between boreal summer insolation and global carbon dioxide (CO2) concentration, which explains the beginning of the past eight glacial cycles and might anticipate future periods of glacial inception. Using an ensemble of simulations generated by an Earth system model of intermediate complexity constrained by palaeoclimatic data, we suggest that glacial inception was narrowly missed before the beginning of the Industrial Revolution. The missed inception can be accounted for by the combined effect of relatively high late-Holocene CO2 concentrations and the low orbital eccentricity of the Earth. Additionally, our analysis suggests that even in the absence of human perturbations no substantial build-up of ice sheets would occur within the next several thousand years and that the current interglacial would probably last for another 50,000 years. However, moderate anthropogenic cumulative CO2 emissions of 1,000 to 1,500 gigatonnes of carbon will postpone the next glacial inception by at least 100,000 years. Our simulations demonstrate that under natural conditions alone the Earth system would be expected to remain in the present delicately balanced interglacial climate state, steering clear of both large-scale glaciation of the Northern Hemisphere and its complete deglaciation, for an unusually long time.

Identification of Aspergillus and Mucorales in formalin-fixed, paraffin-embedded tissue samples: Comparison of specific and broad-range fungal qPCR assays.

Establishing the etiology of invasive fungal infections is important to guide therapeutic options and for epidemiologic purposes. Formalin-fixed, paraffin-embedded (FFPE) tissue specimens from patients with proven invasive fungal infections are valuable to determine the etiology of systemic fungal infections. We compared different polymerase chain reaction (PCR) amplification strategies from FFPE tissue blocks to identify agents of invasive fungal infections. We found that specific PCR assays show superior sensitivity in the identification of DNA of Mucorales and Aspergillus and mixed infections caused by both as compared to broad-range PCR assays. Shorter amplicon lengths and less detection of contaminating fungal DNA are potential factors involved. However, detection of fungal DNA by highly sensitive specific PCR assays in the absence of demonstration of fungal elements in tissue suggests that PCR results should be interpreted in the context of the histopathology and clinical findings.

Increased future ice discharge from Antarctica owing to higher snowfall.

Anthropogenic climate change is likely to cause continuing global sea level rise, but some processes within the Earth system may mitigate the magnitude of the projected effect. Regional and global climate models simulate enhanced snowfall over Antarctica, which would provide a direct offset of the future contribution to global sea level rise from cryospheric mass loss and ocean expansion. Uncertainties exist in modelled snowfall, but even larger uncertainties exist in the potential changes of dynamic ice discharge from Antarctica and thus in the ultimate fate of the precipitation-deposited ice mass. Here we show that snowfall and discharge are not independent, but that future ice discharge will increase by up to three times as a result of additional snowfall under global warming. Our results, based on an ice-sheet model forced by climate simulations through to the end of 2500 (ref. 8), show that the enhanced discharge effect exceeds the effect of surface warming as well as that of basal ice-shelf melting, and is due to the difference in surface elevation change caused by snowfall on grounded versus floating ice. Although different underlying forcings drive ice loss from basal melting versus increased snowfall, similar ice dynamical processes are nonetheless at work in both; therefore results are relatively independent of the specific representation of the transition zone. In an ensemble of simulations designed to capture ice-physics uncertainty, the additional dynamic ice loss along the coastline compensates between 30 and 65 per cent of the ice gain due to enhanced snowfall over the entire continent. This results in a dynamic ice loss of up to 1.25 metres in the year 2500 for the strongest warming scenario. The reported effect thus strongly counters a potential negative contribution to global sea level by the Antarctic Ice Sheet.

[Vascularized tumor of the retroauricular skin]. / Gefäßreicher Tumor der retroaurikulären Haut.

An 84-year-old female patient with loss of hearing and otorrhoea went to an otolaryngologist. On examination, a polypoid mass in the auditory canal and a retroauricular skin lesion, possibly seborrheic keratosis, were found. Only the skin was submitted for histological examination and showed a cutaneous highly vascular lesion with an associated "zellballen" of clear cells without atypia. The initial diagnosis was that of a cutaneous glomangioma. Immunohistochemical findings favored diagnosis of a paraganglioma. Additional clinical information revealed a large mastoid tumor mass. Therefore, the findings were compatible with an jugulotympanic paraganglioma with infiltration of the overlying skin. This possibility was initially not considered in differential diagnosis, as cutaneous glomangiomas are relatively common (typically located on the hands). Cutaneous paragangliomas, however, are not reported.

The peri- and intratumoral immune cell infiltrate and PD-L1 status in invasive squamous cell carcinomas of the penis.

INTRODUCTION: Penile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias. MATERIALS AND METHODS: A cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed. RESULTS: Our study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival. CONCLUSION: PD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy.

Hemorrhagic diathesis associated with benign histiocytic, cytophagic panniculitis and systemic histiocytosis.

Five patients had a histiocytic, cytophagic panniculitis and a febrile, progressive course, which included hepatosplenomegaly, pancytopenia, liver function abnormalities, and a hemorrhagic death. The terminal hemorrhage was characterized by features of intravascular coagulation and liver failure. The histiocytosis could be found at times also in bone marrow, lymph nodes, liver and spleen, and serosal tissues, as well as in skin and subcutaneous tissue. Adequate biopsy diagnosis will prevent such cases from being labeled as Weber-Christian disease with bleeding, and offer an opportunity for appropriate treatment of this new syndrome of histiocytic, cytophagic panniculitis.

Classic Kaposi's sarcoma in Jews living in Israel, 1961-1989: a population-based incidence study.

BACKGROUND: The incidence of classic Kaposi's sarcoma (CKS) has been reported to be high in Jewish populations, mostly born in Eastern Europe. OBJECTIVE: To describe the incidence on CKS in Israeli Jews and to determine differences in incidence according to their geography origin. DESIGN: We analysed data on 1098 incident CKS cases with known country of origin occurring between 1961 and 1989 in the Jewish Israeli population. Reporting systems were the Israel Cancer Registry, the medical documentation of all-Kaposi's sarcoma cases and the registry of HIV-seropositive patients. Patients who were seropositive for HIV were excluded from the study population. Population figures for groups of migrants and natives were derived from census surveys (1961, 1972, 1983) and inter-census estimates based on the population registry. RESULTS: The overall age-standardized rate of CKS was 16.9 per million in men and 6.3 per million in women. The ratio between genders remained stable during the study period. In both genders, there was a steep increase in CKS incidence between the late 1960s (age-standardized rates per million: 8.0 in men and 2.2 in women) and the early 1970s (17.9 in men and 6.7 in women). No further increase was present after 1971. Overall, immigrants experienced a relative risk (RR) of 1.17 [95% confidence interval (CI) 0.90-1.521 compared with Jews born in Israel. Immigrants from Morocco, Algeria and Tunisia had the highest incidence (RR 2.01; 95% CI 1.52-2.65) compared with Jews born in Israel, followed by those born in Iraq (RR 1.74; CI 95% 1.27-2.37). The lowest incidence was experienced by immigrants from Iran (RR 0.37; CI 95% 0.18-0.77) and from Central European countries (RR 0.45; CI 95% 0.30-0.66). Immigrants from other countries in Asia, Africa, the Americas and Europe had similar rates as Jews born in Israel. CONCLUSIONS: Israeli Jews present one of the highest incidences of CKS reported from developed countries. The incidence varies according to geographical origin. Countries surrounding the Mediterranean sea represent the area of highest CKS incidence.

The Merkel cell system and a comparison between it and the neurosecretory or APUD cell system.

The Merkel cell, a neural crest migrant to the skin, possesses a characteristic intranuclear rodlet, cytoplasmic membrane-bound granules, and horn projections and is usually associated with nerve terminations. It is also associated with all types of known organizations of sensory nerve endings in the skin and possesses characteristic enzyme reactions in relation to the ending. The Merkel cell is found in the skin and the oral mucous membranes, and similar cells are observed in the taste buds and pulmonary tissue. A comparison between the Merkel cell and the APUD cell system of polypeptide hormone and amine-producing cells reveals many structural and chemical similarities.

Autotransplantation in pustular psoriasis.

Five women with chronic pustular psoriasis of the soles were subjected to transplantation of full thickness cylinders of tissue between normal glabrous skin and involved plantar skin. Concomitant psoriasis was present in only one of the patients. All patients developed typical pustular psoriasis in normal skin implanted in the foot, while previously involved plantar skin reverted to normal scar when placed in glabrous areas.

New observations in the histopathology of erythema nodosum.

Erythema nodosum presents variable clinical and histologic patterns of response in the vessels, septa, and fat lobules of the subcutaneous tissue. Acute or chronic phlebitis with hemorrhage may be commonly observed; acute panniculitis is observed in foci, but at time it may be the principal histologic feature; lymphocytic infiltration of fat lobules is often found, and lymphoid nodules are not infrequent; rarely, chronic granulomatous lesions involve septa or fat lobules; and proliferative lipocyte response may be observed. Because these variable histologic patterns may be coexistent, excision biopsy and multiple sections are necessary to recognize them. The variable histologic features correlate with the different clinical forms: acute nodular, chronic nodular, migrating plaque lesion, cellulitis, and the rate suppurative form. This variety of panniculus response in erythema nodosum can be explained on the basis of host-tissue response to a delayed hypersensitivity reaction to an antigenic stimulus.

Cutaneous neuropathology in multiple endocrine neoplasia, type 2b.

Increase in masses of mixed (myelinated and nonmyelinated) nerve are observed in the dermis of clinically normal skin of patients with multiple endocrine neoplasia, type 2b (MEN 2b). Preliminary histochemical studies revealed nucleoside triphosphatase and nonspecific acid esterase. Electron microscopy showed axonal organelles, mild degeneration of axons, and numerous axons unassociated with Schwann cells. The normal-appearing skin in MEN 2b seems to contain abnormal nerve tissue development equally with the mucosal and the gastrointestinal tract.

The human cutaneous basement membrane--anchoring fibril complex: preparation and ultrastructure.

The human cutaneous basement membrane (CBM) has been isolated together with the anchoring fibrils (AF) of the dermis. These structures are removed from the dermis as a single complex, the CBM-AF complex. The epidermis is first removed from the dermis by immersion of whole, defatted skin in cold 2 n NaSCN for 5 to 6 hr. Subsequently, removal of the CBM-AF complex is effected by focusing high-intensity ultrasonic energy against the dermal surface. Purification of the preparation is achieved by low-speed sedimentation. All stages of the process were monitored by electron microscopy, which demonstrated that the morphology of the CBM-AF complex was well preserved and that this complex represents the principal mass component in the system. In addition, our report describes an ultrasound-induced variation in collagen fibril morphology, which we have called 'disordered collagen.' This altered type of fibril lacks periodicity or recognizable banding and has a frayed appearance. Finally, the experiments provide the basis for an analysis of the relative strengths of certain bonds at the dermal--epidermal junction. The strongest of these appears to be the bond between basement membrane and anchoring fibril.

IgE in human eccrine sweat.

By the use of a sensitive and specific double antibody radioimmunoassay, immunoglobulin E was demonstrated in sweat from 6 of 11 healthy volunteers; the concentrations of IgE ranged from 1 to 3.9 ng/ml of sweat. Six of seven patients with dermatitis and elevated levels of serum IgE also had high IgE levels in sweat; the highest IgE value in sweat was 75.5 ng/ml and was noted in a patient with atopic dermatitis. Thus, all the main immunoglobulin classes can be demonstrated in eccrine sweat.

Lipid synthesis in cutaneous xanthoma.

In vitro lipogenesis was studied on the xanthoma tissue from 6 patients with normal plasma lipids and 4 patients with hyperlipidemia. Xanthoma tissue was incubated at 37 degrees C for 6 hr in Krebs-Ringer phosphate buffer containing sodium [14C]acetate. The radioactivity of each lipid class was determined after extraction and separation of lipids. The incorporation of acetate into all major lipid groups was much greater in xanthoma tissue than in control normal-appearing skin. There was no difference in the incorporation pattern of 14C between xanthomas of patients with normal plasma lipids and those of hyperlipidemic patients. The data exemplify considerable in situ lipid synthesis of xanthoma tissue. Although the lipids in xanthomas of hyperlipidemic persons may be derived from plasma, the plasma origin of xanthoma lipids in normolipidemic persons remains to be confirmed, and the contribution of local lipogenesis cannot be ignored. The lipids in cutaneous xanthomas are most likely derived from a multiple input system.

Prostaglandins and chemotaxis: enhancement of polymorphonuclear leukocyte chemotaxis by prostaglandin F2alpha.

Prostaglandins E1, E2, F1alpha, and F2alpha did not demonstrate direct in vitro chemotactic properties either to rabbit peritoneal polymorphonuclear leukocytes or to rabbit or human polymorphonuclear leukocytes isolated from blood. Prostaglandin F2alpha, however, enhanced the chemotactic responsiveness of human polymorphonuclear leukocytes to the chemotactic agent casein.

Inflammation in acne vulgaris: leukocyte attraction and cytotoxicity by comedonal material.

The chemoattraction of comedonal material for leukocytes was evaluated. Material from open comedones attracted mononculear leukocytes but did not attract polymorphonuclear leukocytes. At higher concentrations, comedonal material was cytotoxic for leukocytes of both types. Of the comedonal components tested, free fatty acids produced the greatest cytotoxicity. The attraction and killing of leukocytes by comedonal components may be the mechanisms for the initiation or the enhancement (or both) of inflammation in acne vulgaris.

Dermal mast cell activation by autoantibodies against the high affinity IgE receptor in chronic urticaria.

Previous studies identified autoantibodies against the IgE high affinity receptor alpha-chain, Fc epsilon RI alpha, in sera of selected patients with severe chronic idiopathic urticaria. We have now determined the incidence of anti-Fc epsilon RI alpha autoantibodies in a group of 163 patients. Intradermal injection of autologous serum caused skin reactions indicative of mast cell degranulation in 98 (60%) patients. Based on histamine release from IgE-sensitized and nonsensitized basophil leukocytes of healthy donors, we detected anti-Fc epsilon RI alpha autoantibodies in sera from 38 (23%) urticaria patients and evidence for anti-IgE antibodies in a further nine patients. The sera that released histamine from basophils induced histamine release (4-34%, n = 12) from mast cells in incubated skin slices. Protein-G affinity chromatography of sera demonstrated that mast cell histamine release was IgG-mediated. Preincubation of sera or the IgG fraction with a recombinant alpha-chain of Fc epsilon RI inhibited histamine release from mast cells and basophils. Further studies with the mouse anti-human Fc epsilon RI alpha antibody 29C6 showed that mast cells and basophils were similarly sensitive to IgG-mediated direct cross-linking of Fc epsilon RI, with 0.01-1.0 micrograms/ml 29C6 evoking histamine release in each case. These studies demonstrate that circulating levels of anti-Fc epsilon RI alpha autoantibodies mediate histamine release from skin mast cells in vitro and, taken together with in vivo evidence of mast cell degranulation following intradermal injection of autologous serum, support the concept that anti-Fc epsilon RI alpha autoantibodies are relevant to the pathogenesis of severe chronic urticaria in about 25% of patients.

Necrobiotic xanthogranuloma with paraproteinemia. A review of 22 cases.

Cutaneous biopsy specimens from 22 patients showed the distinctive histopathologic pattern of necrobiotic xanthogranuloma within the dermis or subcutaneous tissue (or both). Twenty of the 22 patients had 1 or more serum protein abnormalities, consisting of an IgG monoclonal protein in 16, multiple myeloma in 3, cryoglobulinemia in 3, and an abnormal serum protein electrophoresis in 1. Cutaneous lesions were seen as discrete, slowly developing red nodules and plaques with a xanthomatized hue and a predilection for the face (periorbital region in particular), trunk, and extremities. Ulceration was a notable finding in 10 patients. Histologically, the dermis and lobules of subcutaneous tissue were involved with a granulomatous infiltrate containing bands of hyaline necrobiosis and bizarre foreign body, as well as Touton giant cells. Cholesterol clefts, lymphoid nodules with or without germinal centers, and foci of plasma cells were variable but significant features. Leukocyte monoclonal antibody studies in 6 patients demonstrated helper T cells within the granulomas. Electron microscopy in 3 cases showed lipid vacuoles in macrophages in the dermis and dendritic cells in the epidermis, and study confirmed this entity as a non-X histiocytosis. Pertinent laboratory findings, in addition to the serum protein abnormalities, included elevation of the erythrocyte sedimentation rate, leukopenia with absolute neutropenia, and decreased serum complement levels, as well as decreased levels of C1-esterase inhibitor in some patients. Thirteen of the 22 patients have survived, the mean duration being 9.5 years after the onset of cutaneous disease. While given to only a few patients in the current series, low-dose chemotherapy seems to induce a favorable response in both the cutaneous and the hematologic disease.

Acral arteriovenous tumor. A clinicopathologic review.

We reviewed 47 cases of a distinctive, benign vascular tumor, acral arteriovenous tumor. Study of the clinical histories of patients with this tumor emphasized the difficulty of making a clinical diagnosis. Most of the tumors were asymptomatic and were found in generally healthy middle-aged or elderly male patients. Distribution was acral; 79% of the tumors were located on the head or extremities. Histologic study showed a component of capillary nevus in some cases in addition to the typical venous and arteriovenous channels.

Treatment of lichen planus.

Lichen planus is an inflammatory pruritic dermatosis in which T lymphocytes attack the basal epidermis, producing characteristic clinical and histological lesions. Mild cases can be treated successfully with rest, topical corticosteroids with or without wet dressings, or occlusion. Severe generalised cases may require systemic corticosteroids. Chronic, aggressive lesions may need additional therapy ranging from psoralen plus ultraviolet A (PUVA) to retinoids or cyclosporin. Complications ranging from infectious, bullous disease or ulceration require special treatment considerations.