Squamous dysplasia of the uterine cervix: tissue sampling-related diagnostic considerations in 600 consecutive biopsies.

Despite the technological advances in colposcopic techniques, there continues to be a 10% to 20% discordance rate between the colposcopic findings and the histological diagnoses on the resultant biopsies. One of the many factors to which this may be theoretically attributable is related to sampling error from the paraffin-embedded tissue block. In this study, we evaluated the clinical efficacy of routinely obtaining 6 sections in cervical biopsies, using the frequency with which dysplastic lesions would be missed with various levels of sectioning as the sole benchmark determinant of clinical efficacy. Our database was searched for all cervical biopsies in which a diagnosis of squamous dysplastic lesion was made for the period February 1, 2006 to April 28, 2006. All cases were processed in 6-level sectioning, which entails cutting and staining (hematoxylin-eosin) 6 consecutive sections from the paraffin block without preserving or discarding any intervening unstained sections. The first level at which a diagnosis of dysplastic lesion could be unequivocally made by a gynecologic pathologist was determined. Six hundred consecutive biopsies from 404 patients were reviewed. For the whole cohort, the average level at which a dysplastic lesion was unequivocally diagnosable was 1.9 (median, 1). Three hundred fifty-seven (59.5%), 97 (16.2%), 41 (6.8%), 55 (9.2%), 34 (5.7%), and 16 (2.6%) of the 600 lesions were diagnosable at levels 1, 2, 3, 4, 5, and 6, respectively. The cervical intraepithelial neoplasia (CIN) 2 and 3 (n = 89) was, on average, diagnosable at an earlier level (1.35) compared with CIN 1 (level, 2.025; P < 0.001 [n = 511]). Indeed, 79.8% of the CIN 2-3 cases were diagnosable at level 1, as compared with 56% of the CIN 1 cases (P < 0.001); 87, 38, 52, 32, and 16 cases of CIN 1 and 10, 3, 3, 2, and 0 cases of CIN 2-3 were diagnosable at levels 2, 3, 4, 5, and 6, respectively. Therefore, if sectioning were limited to 3 levels, 17.5% (105/600) of all dysplastic lesions would have been missed, including 19.6% (100/511) of CIN 1 and 5.6% (5/89) of CIN 2-3. Because not more than 3 levels are routinely evaluated in most laboratories, our findings suggest that sampling error is indeed at least 1 significant factor contributing to colposcopic/histological discrepancies. Using our clinical efficacy standard, when no pathologic findings are initially identified in a colposcopic-directed biopsy, at least 5 levels (a priori or in recuts) are required to ensure a 100% diagnostic accuracy for CIN 2-3.     

Gastric mucosal calcinosis: clinicopathologic considerations

Generally, gastric mucosal calcinosis (GMC) is only rarely encountered in routine biopsies. GMC may be classified as dystrophic, metastatic, or idiopathic. Metastatic calcification represents the most frequently encountered subtype, and refers to the deposition of calcium salts on largely normal tissues in the setting of an abnormal serum biochemical environment (hypercalcemia, hyperphosphatemia, and/or an elevated CaxPO4 product). In contrast, dystrophic calcification implies calcification in inflammed, fibrotic, or otherwise altered tissue in the setting of a normal biochemical environment. The gastric mucosa, along with the kidneys and lungs, are preferential sites for metastatic calcification, a finding that has been attributed to the relative intracellular alkalinity at these sites. In addition to the wide variety of hypercalcemia and/or hyperphosphatemia-causing clinical conditions, GMC has also been associated with atrophic gastritis, hypervitaminosis A, organ transplantation, gastric neoplasia, uremia with eucalcemia/euphosphatemia, and the use of aluminum-containing antacids, citrate-containing blood products, isotretinoin, and sucralfate. Although GMC has rarely been associated with epigastric pain and/or dyspepsia, most come to clinical attention owing to their accumulation of bone-seeking radiopharmaceuticals or represent a postmortem finding. The precise significance or mechanistic basis for GMC remains to be elucidated. However, their presence in gastric biopsies should be reported, as they may serve as an indicator for generalized metastatic calcification, especially in organs where they may be fatal, such as the heart. Furthermore, some examples of systemic calcification are reversible with normalization of biochemical parameters, which highlights the need for pathologists to report this finding when encountered in a premortem gastric biopsy.     

Cyclical konzo epidemics and climate variability

Konzo epidemics have occurred during droughts in the Democratic Republic of Congo (DR Congo) for >70 years, but also in Mozambique, Tanzania, and the Central African Republic. The illness is attributed to exposure to cyanide from cassava foods, on which the population depends almost exclusively during droughts. Production of cassava, a drought‐resistant crop, has been shown to correlate with cyclical changes in precipitation in konzo‐affected countries. Here we review the epidemiology of konzo as well as models of its pathogenesis. A spectral analysis of precipitation and konzo is performed to determine whether konzo epidemics are cyclical and whether there is spectral coherence. Time series of environmental temperature, precipitation, and konzo show cyclical changes. Periodicities of dominant frequencies in the spectra of precipitation and konzo range from 3 to 6 years in DR Congo. There is coherence of the spectra of precipitation and konzo. The magnitude squared coherence of 0.9 indicates a strong relationship between variability of climate and konzo epidemics. Thus, it appears that low precipitation phases of climate variability reduce the yield of food crops except cassava, upon which the population depends for supply of calories during droughts. Presence of very high concentrations of thiocyanate (SCN^?), the major metabolite of cyanide, in the bodily fluids of konzo subjects is a consequence of dietary exposure to cyanide, which follows intake of poorly processed cassava roots. Because cyanogens and minor metabolites of cyanide have not induced konzo‐like illnesses, SCN^? remains the most likely neurotoxicant of konzo. Public health control of konzo will require food and water programs during droughts. [Correction added on 26 February 2015, after first online publication: abstract reformatted per journal style] Ann Neurol 2015;77:371–380     

Comparative Cytotoxicity of Glycyrrhiza glabra Roots from Different Geographical Origins Against Immortal Human Keratinocyte (HaCaT), Lung Adenocarcinoma (A549) and Liver Carcinoma (HepG2) Cells

Glycyrrhiza glabra L. (Fabaceae), commonly known as ‘liquorice’, is a well‐known medicinal plant. Roots of this plant have long been used as a sweetening and flavouring agent in food and pharmaceutical products, and also as a traditional remedy for cough, upper and lower respiratory ailments, kidney stones, hepatitis C, skin disorder, cardiovascular diseases, diabetes, gastrointestinal ulcers and stomach ache. Previous pharmacological and clinical studies have revealed its antitussive, antiinflammatory, antiviral, antimicrobial, antioxidant, immunomodulatory, hepatoprotective and cardioprotective properties. While glycyrrhizin, a sweet‐tasting triterpene saponin, is the principal bioactive compound, several bioactive flavonoids and isoflavonoids are also present in the roots of this plant. In the present study, the cytotoxicity of the methanol extracts of nine samples of the roots of G. glabra, collected from various geographical origins, was assessed against immortal human keratinocyte (HaCaT), lung adenocarcinoma (A549) and liver carcinoma (HepG2) cell lines using the in vitro 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl tetrazoliumbromide cell toxicity/viability assay. Considerable variations in levels of cytotoxicity were observed among various samples of G. glabra. Copyright © 2015 John Wiley & Sons, Ltd.     

Indoor air pollution from biomass fuels: a major health hazard in developing countries

Background

Nearly 3 billion people live without electricity today. This energy poverty means that they have to resort to biomass fuels for their household energy needs. When burned, these fuels release a mixture of toxic chemicals in their smoke, which is often over twenty times greater than World Health Organization (WHO) and Environmental Protection Agency recommended guideline limits.

Aim

This review details factors that contribute to indoor air pollution, its effects on health, and discusses corrective measures to consider when planning intervention strategies to stem the high morbidity and mortality trend.

Methods

The term developing countries is defined using the 2008 United Nations Conferences on Trade and Development Handbook. PubMed, Google Scholar and Science Direct databases from 1990 to 2011 were searched using the key terms: indoor air pollution, biomass fuel, particulate matter, health risks, and developing countries. Bibliographies of all relevant articles were also screened to find further eligible articles. Inclusion criteria were peer-reviewed articles and technical reports from global health organizations such as the WHO and United Nations Development Program. Exclusion criteria were articles focused on modern energy, developed countries, and non-English publications.

Results

The review discusses the extent of indoor air pollution related to use of biomass for cooking and assesses its impact on various health and social problems, including lung diseases, adverse pregnancy outcomes and human development, especially in vulnerable populations. It also offers strategies to mitigate problems related to indoor air pollution.

Conclusions

Biomass fuel is a major cause of indoor air pollution and is a significant health hazard in developing countries. A thorough understanding of the connection between choice of fuel for household needs and health impact of long-term exposure to pollutants from smoke generated during use of biomass for cooking is required so that appropriate intervention strategies and policies can be established to protect vulnerable populations.     

Prevention of graft-versus-host disease and bone marrow rejection: kinetics of induction of tolerance by UVB modulation of accessory cells and T cells in the bone marrow inoculum

UVB irradiation (700 J/m2) of bone marrow cells (UVB-BMC) before transplantation into lethally gamma-irradiated (10.5 Gy) allogeneic rats prevents graft-versus-host disease (GVHD) and induces a stable complete lymphohematopoietic chimerism. To better understand the underlying mechanism of the development of stable chimerism and induction of tolerance to donor organs in this model, we examined if the addition of T cells or dendritic cells (DC), as antigen presenting cells (APC), would restore the immunogenicity of UVB-BMC in in vitro mixed lymphocyte reaction (MLR) and induce in vivo bone marrow (BM) graft rejection. Whereas gamma-irradiated, unfractionated BMC induce allogeneic T cells to proliferate, UVB irradiation of BMC abolishes the stimulatory capacity of such cells in a primary MLR. Addition of purified T cells, CD4+ T cells, CD8+ T cells or B cells, respectively, failed to restore the capacity of UVB-BMC to stimulate allogeneic T- cell proliferation. In contrast, the addition of only a small number of splenic accessory cells or purified DC, which by themselves were relatively ineffective in stimulating T-cell proliferation, restored the accessory function and the allostimulatory capacity of UVB-BMC. To define the molecular defect induced by UVB irradiation, cytokines were added as costimulatory factors to primary MLRs and the results showed that the addition of interleukin (IL)-2 or IL-6 but not IL-1 or interferon gamma (IFN-gamma) restored the stimulatory capacity of UVB BMC. This finding suggests that UVB may alter the production, and/or utilization of IL-2 and IL-6 either at the membrane or cytoplasmic level. Parallel in vivo studies showed that addition of DC to UVB BM inoculum resulted in failure of BM engraftment, whereas addition of T cells led to development of fatal GVHD, thus suggesting that UVB modulation of accessory cells reduces graft immunogenicity and prevents BMT rejection, while modulation of T cells prevents GVHD. Our data provide evidence that UVB modulation of APC and mature T cells contained within BMC is potentially useful in preventing GVHD without endangering successful engraftment and may serve as a model for induction of adult chimerism and tolerance without the development of GVHD.     

Functional characterization of α1-adrenoceptor subtypes in the rabbit spleen

Phenylephrine and (±)N-[5-(4,5-dihydro-1-H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulphonamide hydrobromide (A 61603) evoked concentration-dependent contractions of the rabbit spleen. These contractions were antagonized by prazosin (10^–8–10^–7 M) with pA ₂ values of 8.34±0.11 and 8.15±0.10 against phenylephrine and A 61603, respectively. In both cases, the slopes of the Schild plots were not significantly (P>0.05) different from 1.0, indicating competitive antagonism. The effects of subtype-selective antagonists WB 4101 [2-(2-6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride] and 5-methylurapidil on agonist-induced contractions were also examined. WB 4101 competitively antagonized agonist-induced contractions; pA ₂ values were 8.13±0.10 and 8.10±0.03 against phenylephrine and A 61603, respectively. Corresponding values for 5-methylurapidil were 8.28±0.17 and 7.93±0.02 against phenylephrine and A 61603, respectively. Tamsulosin and Rec 15/2739 [(8-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride] also antagonized phenylephrine- and A 61603-induced contractions with pA ₂ values of 9.38±0.13 and 9.18±0.06 (tamsulosin) and 8.41±0.12 and 8.34±0.11 (Rec 15/2739) against phenylephrine and A 61603, respectively. HV 723 (α-ethyl-3,4,5-trimethoxy-α-(3-((2-(2-methoxyphenoxyethyl)-amino)-propyl)benzene-aceto-nitrile) fumarate) competitively antagonized phenylephrine-induced contractions with a pA ₂ value of 8.57±0.06. Chloroethylclonidine (CEC; 10^–4 M) shifted phenylephrine and A 61603 concentration-response curves to the right, reducing their potencies approximately two- to threefold, while the maximum response was reduced by 8% in both cases. It was therefore concluded that contractions of the rabbit spleen induced by α₁-adrenergic agonists were mediated predominantly by a relatively CEC-insensitive α₁-adrenoceptor subtype, possibly the α_1L-subtype. Received: 14 April 1998 / Accepted: 17 June 1998