Early intervention and disease modification in atopic dermatitis-the current state of the field and barriers to progress.

Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease representing a major source of global disability burden. Disease-modifying therapies are showing promise in chronic inflammatory disorders such as rheumatoid arthritis and Crohn's disease with method and timing of initial treatment impacting long-term disease outcomes. Whether disease-modifying therapies, specifically those used as an early interventional approach, impacts disease course and comorbidity development in AD is not well-understood. We reviewed the progress in disease modification strategies, emphasizing early intervention approaches in common (or proto-typical) inflammatory diseases. Although more common in other fields, disease modification approaches are becoming increasingly investigated in dermatology, though studies in AD are lacking. Despite significant limitations in ongoing and completed studies, early data are promising and suggest that both the choice and timing of early intervention approach can affect long-term disease course and comorbidity development. To best improve AD patient outcomes, more research is needed to further explore the impact of early disease-modifying therapies. Future studies should focus on identifying the most effective approaches and extend the early results to a more inclusive set of comorbidities and longer-term outcomes.

Swallowing problems in post irradiated NPC patients.

We present three patients with Nasopharyngeal Carcinoma (NPC) developing swallowing problems after radiotherapy as the primary modality of treatment. All patients had advanced stage NPC presenting with enlarged neck nodes and underwent radical external beam radiotherapy. All three patients had both CN X and CN XII palsies and had difficulty in both the oral and pharyngeal phases of swallowing. None of them has any clinical or radiological evidence of local recurrence in the post nasal space and neck or metastasis to the skull base. One patient underwent cricopharyngeal myotomy with epiglottopexy and hyoid suspension which failed and subsequently underwent laryngectomy. Another patient had medialisation thyroplasty and the third underwent a percutaneous endoscopic gastrostomy (PEG).

Increased mutation frequency following treatment with cancer chemotherapy.

The relationship between somatic mutation and cancer was studied by measuring in vivo mutation frequency and in vitro mutability using lymphocytes from 28 untreated adult patients with solid tumors, 14 untreated patients with lymphoma, and 27 patients with solid tumors or lymphoma who had been treated with chemotherapy and/or radiotherapy. In vivo mutation frequency in untreated patients did not differ from that of controls, except perhaps in patients with lymphoma, who showed a slight increase. Lymphocytes from untreated patients with solid tumors or lymphoma did not show a greater increase in mutations induced after X-radiation or UV radiation than did lymphocytes from controls. For all the untreated patients, the geometric mean mutation frequency was 6.72 X 10(-6), and it was significantly increased to 19.57 X 10(-6) following chemotherapy and 34.40 X 10(-6) following chemotherapy and radiotherapy. The results suggest that excessive systemic exposure to mutagens or inherent susceptibility to mutagenesis are not important etiological factors in at least the majority of patients with cancer. The mutations produced by treatment may be related to the late side effects of therapy such as second neoplasms.

The cells of origin of lymphocyte clones grown by limiting dilution.

A high proportion of the mononuclear cells separated from peripheral blood by Ficoll-Hypaque centrifugation show extensive proliferation when cloned at limiting dilution. The nature of clone-forming cells ( CFCs ) and the cells generated during clone formation were studied by cytotoxicity with antibody and complement and by immunofluorescence. Cytotoxicity prior to cloning with OKT3 plus OKT11 eliminated 99.34% of clones, indicating that virtually all CFCs are T-lymphocytes, and cytotoxicity with OKT4 or OKT8 indicated that helper and suppressor subclasses each contribute approximately half of the CFCs . Immunofluorescence of cells proliferating in clones confirmed that all clones were T-lymphocytes and showed that 47% were OKT4 positive and 47% were OKT8 positive; 6% were negative with both OKT4 and OKT8. The results indicate that in the nearly optimal conditions for proliferation provided by limiting dilution, clones arise entirely from T-lymphocytes and clone formation is a property of a variety of lymphocyte subclasses.

Radiation sensitivity of human lymphocytes.

A simple and rapid in vitro technique to assess the sensitivity of human lymphocytes to X- and UV-radiation is described. Peripheral blood lymphocytes are cloned in agar and colony survival is used as the end point. Survival down to a fraction of approx. 0.02 can be measured accurately. The D10 for X-radiation is approx. 165 rad and the initial portion of the survival curve is linear with no evidence of a threshold. The D10 for UV-radiation is approx. 50 erg/mm2. The technique should be of value both for general radiobiological studies and for detecting individuals having abnormalities of DNA repair.

A proliferative defect of marrow cells in experimental chronic hypoplastic marrow failure (aplastic anaemia).

Marrow cells from control mice and mice with chronic hypoplastic marrow failure (CHMF, aplastic anaemia) were grown in tissue culture and growth was assessed by measuring the number of cells/colony and uptake of 3H-thymidine/colony. Cells from mice with CHMF showed impaired proliferation in response to colony stimulating factor. Mixing experiments suggested that the impairment of proliferation was not dut to alteration in suppressor or helper cells but to an intrinsic lesion of the marrow cells themselves.

Effective use of blood in elective surgical procedures.

The preoperative requests for crossmatching of blood in elective surgical procedures were studied at the Flinders Medical Centre, South Australia. The study revealed that surgeons order crossmatched blood on the basis of habit. This led to considerable time-expiry of blood, and to unnecessary use of laboratory personnel's time and reagents. The statistical information collected during the study was used to educate the surgeons to change their blood-ordering practice. In procedures where excessive blood loss is unlikely to occur, as a stand-by, a "group-and-screen" procedure was substituted for crossmatching. A firm recommendation for maximum blood order in elective surgical procedures was also made. It is estimated that this approach would save approximately $80,000 per year per 350-bed general hospital in Australia.

Chronic hypoplastic marrow failure and residual injury.

An experimental model of chronic marrow failure can be produced in mice by treatment with a short course of busulphan. This results in permanent partial marrow failure which may later progress and become complete. The underlying lesion appears to be stem cell damage which leads to failure of proliferation of stem cells and their progeny. Other drugs can produce the same lesion and alkylation of DNA may be the mechanism.

Leukocyte density and volume in normal subjects and in patients with acute lymphoblastic leukemia.

A method is described for the separation of blood and bone marrow leukocytes on the basis of buoyant density, using a discontinuous Ficoll-Hypaque density gradient. The median cell densities of monocytes and lymphocytes were found to be 1.067-1.077 and 1.073-1.077 g/ml, respectively. The cells of the myeloid series were shown to increase in density with maturation; the myeloblasts had the lowest density (1.064-1.065 g/ml) and the neutrophils the highest (greater than 1.080 g/ml). Cell volumes have been determined on isolated cell populations. The findings were: monocytes, 534 +/- 47 cu mu; lymphocytes, 247 +/- 18 cu mu; and neutrophils, 468 +/- 24 cu mu. Fourteen patients with acute lymphoblastic leukemia were studied. In four patients, the lymphoblasts were of low density (less than 1.068 g/ml), whereas the remaining patients had high density (greater than 1.068 g/ml) lymphoblasts. These four patients had large numbers of lymphoblasts in the peripheral blood and a poor prognosis. Lymphoblast volumes were not different in these two groups and were unrelated to prognosis.

Leukemic reticuloendotheliosis. A failure of monocyte production.

In five cases of leukemic reticuloendotheliosis studied, profound monocytopenia was demonstrable. In 48 normal subjects, monocyte counts ranged from 215 to 921 per cubic millimeter, whereas in the five patients with leukemic reticuloendotheliosis, the counts ranged from 0 to 17 per cubic millimeter. The properties of the "hairy" cell are consistent with those of an incompletely developed monocyte. The susceptibility to infection, characteristics of these patients, may result from a lack of normal monocytes in blood and tissues.