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PubMed1978

Hairy cell leukemia: an unusual lymphoproliferative disease: a study of 24 patients.

A laboratory and clinical evaluation of 24 patients with hairy cell leukemia was carried out over a 23-month period. Most patients had splenomegaly without adenopathy or pancyotpenia. Nine of the patients had undergone splenectomy prior to referral; their median WBC count was 6600/mm3. The median WBC count for the 14 patients who had no prior therapy was 3550/mm3, and their median platelet count was 80,500/mm3. Spleen weights ranged from 618 to 3780 g; there appeared to be no relationship between the size of the spleen and the response in the blood counts after splenectomy. Four patients in whom the majority of the WBC were hairy cells underwent splenectomy, which produced no real change in their WBC count; however, there was improvement in the platelet count in three. In contrast, the presence of leukopenia with a low percentage of hairy cells predicted a beneficial response to splenectomy. The study of surface immunoglobulins (SIg) in 16 patients demonstrated that resynthesis had occurred in each case. Phagocytosis of zymosan was studied in 15 patients; in 8 of these, 25% or more of the hair cells were capable of phagocytosis; in 6 others, 0--9%; and in one, 13%. The resynthesis of SIg is a feature usually associated with B-lymphocytes, but the phagocytosis of zymosan is not. Thus, the existence of either a spectrum of functional capabilities of hairy cells or several distinct subtypes is suggested by these data. Platelet aggregation with epinephrine was abnormal in 7 of 14 patients studied but there were no clinically significant bleeding problems. A chromosome abnormality was present in 2 of the 19 patients from whom adequate samples were obtained; the abnormality probably involved chromsome 12 in both patients as well as absent Y and was associated with a rapidly progressive clinical course. The presence of a predominant number of hairy cells with a normal or increased peripheral blood WBC count or of a chromosomal abnormality suggests that splenectomy might not be beneficial as the initial therapy and that chemotherapy should be considered.

Acid Phosphatase↗

PubMed1988

Descriptive and analytic epidemiology. Bridges to cancer control.

Epidemiology serves as a bridge between basic science and cancer control. The two major orientations of epidemiology are descriptive and analytic. The former is useful in assessing the scope and dimensions of the cancer problem and the latter is used to assess environmental and lifestyle sources of cancer risk. A recent development in descriptive epidemiology is the use of functional measures of disease such as lost life expectancy. In analytical epidemiology, there is new or renewed interest in several lifestyle factors including diet and exercise as well as environmental factors such as involuntary tobacco exposure and radon in dwellings. Review of the evidence should consider the strengths and weaknesses of different research procedures. Each method is inconclusive by itself but, the different research designs of epidemiology collectively may represent a hierarchy of proof. Although the roles of many factors remain to be defined, the aggregate epidemiologic data continue to demonstrate the special importance of personal behavior and lifestyle in affecting cancer risk.

Diet↗

PubMed2000

First steps in analysing NHS waiting times: avoiding the 'stationary and closed population' fallacy.

The aim of this paper is to demonstrate the effect of excluding incomplete observations and competing events when calculating cross-sectional measures of NHS waiting times, and to obtain a more accurate estimate of the 'time-to-admission' of those listed on NHS waiting lists using life-table methods. The official 'times-since-enrollment' of all elective 'admissions' in England, 1 July to 31 December 1994 inclusive, were extracted from Hospital Episode Statistics. The official 'times-to-census' of all those on a waiting list in England at 30 September 1994 were obtained from aggregated KH07 data. The percentage waiting at least three months, at least six months etc., was calculated separately for each data set and compared with a period life-table derived from the combined data. The cumulative likelihood of elective admission is markedly overestimated across the whole range of waiting times. The experience of those still waiting, those removed from the list, those suspended or deferred and those put to the back of the queue is not taken into account in the calculation of official waiting times. The Department of Health currently presents the 'time-since-enrollment' of those admitted as though it indicates how long all patients can expect to wait for admission. The consequent bias in published summary statistics incorrectly quantifies the real experience of patients. It is recommended that calculation of waiting times from KH07 census counts and Hospital Episode Statistics be reconsidered in the light of what patients, clinicians, managers and politicians need to know about treatment delay.

Bias↗

PubMed1982

The sick and the dead: the development of psychological theory on necrophilia from Krafft-Ebing to the present.

Researchers dealing with necrophilia over the past century have conducted their investigations using a great variety of methodological strategies and theoretical formulations. The multiplicity of approaches has been partially responsible for the diverse nature of speculations on the etiology, essence, and evolution of necrophilia, and for the accumulation of case histories and an aggregation of data from which it is exceedingly difficult to draw generalizations. There are only two assumptions on which most of the investigators agree. One is that necrophilia is exceedingly rare. The other is that the literature on the subject is severely limited. This paper not only questions the first assumption but establishes that the second is demonstrably false. It also attempts to locate some measure of constancy among the several theoretical lines on necrophilia that have emerged since the time of Krafft-Ebing, to evaluate their effect on scholarship, and to provide some sense of the directions taken by more recent investigators.

Attitude to Death↗

PubMed2003

Molecular mechanisms of Fe2+-induced beta-lactoglobulin cold gelation.

To get more insight into the mechanisms of cold gelation of beta-lactoglobulin (beta-lg), macroscopic and molecular structural changes during Fe(2+)-induced gelation of beta-lg were investigated using Fourier transform-infrared (FTIR) spectroscopy and rheological methods. The FTIR spectroscopy results show that, upon the preheating treatment (first step of gel process), native globular proteins are denatured and aggregated molecules are found in solution. The spectra are similar to those of gels obtained in the second step of the process upon incorporation of Fe, which suggests that aggregated molecules formed during the preheating treatment constitute the structural basis of the aggregation. However, the rheological data show that the aggregation is achieved via two molecular mechanisms, both of which are modulated by the iron concentration. At 30 mM of iron, gel formation is essentially controlled by van der Waals interactions, while at 10 mM of iron, hydrophobic interactions predominate. At the two concentrations, disulfide bonds contribute to gel consolidation, the effect being more pronounced at 10 mM of iron. These mechanisms lead to the formation of gels of different microstructures. At the highest iron concentration, a strong and rapid decrease in the repulsion forces is produced, resulting in random aggregation. At the lowest iron concentration, the iron diminishes the superficial charge of both molecules and aggregated molecules, facilitating the interaction among hydrophobic regions and leading to the growth of the aggregation in the preferential direction and to filamentous gel formation. This study provides a comprehensive view of the different modes of gelation.

Animals↗

PubMed2005

Humoral and contact interactions in astroglia/stem cell co-cultures in the course of glia-induced neurogenesis.

Astroglial cells support or restrict the migration and differentiation of neural stem cells depending on the developmental stage of the progenitors and the physiological state of the astrocytes. In the present study, we show that astroglial cells instruct noncommitted, immortalized neuroectodermal stem cells to adopt a neuronal fate, while they fail to induce neuronal differentiation of embryonic stem cells under similar culture conditions. Astrocytes induce neuron formation by neuroectodermal progenitors both through direct cell-to-cell contacts and via short-range acting humoral factors. Neuron formation takes place inside compact stem cell assemblies formed 30- 60 h after the onset of glial induction. Statistical analyses of time-lapse microscopic recordings show that direct contacts with astrocytes hinder the migration of neuroectodermal progenitors, while astroglia-derived humoral factors increase their motility. In non-contact co-cultures with astrocytes, altered adhesiveness prevents the separation of frequently colliding neural stem cells. By contrast, in contact co-cultures with astrocytes, the restricted migration on glial surfaces keeps the cell progenies together, resulting in the formation of clonally proliferating stem cell aggregates. The data indicate that in vitro maintained parenchymal astrocytes (1) secrete factors, which initiate neuronal differentiation of neuroectodermal stem cells; and (2) provide a cellular microenvironment where stem cell/stem cell interactions can develop and the sorting out of the future neurons can proceed. In contrast to noncommitted progenitors, postmitotic neuronal precursors leave the stem cell clusters, indicating that astroglial cells selectively support the migration of maturing neurons as well as the elongation of neurites.

Animals↗

PubMed1997

In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset.

Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by destruction of the intrahepatic bile ducts. It is generally believed that cellular immune mechanisms, particularly involving T cells, result in this bile duct damage. The relative strength of Th1 and Th2 responses has recently been proposed to be an important factor in the pathophysiology of various autoimmune diseases. In this study, we have attempted to identify the Th subset balance in PBC, by detection of cytokines specific to the two T-cell subsets, i.e., interferon gamma (IFN-gamma) for Th1 cells and interleukin-4 (IL-4) for Th2 cells. We analyzed IFN-gamma and IL-4 messenger RNA (mRNA) positive cells in liver sections from 18 patients with PBC and 35 disease controls including chronic active hepatitis C, extrahepatic biliary obstruction (EBO), and normal liver, using nonisotopic in situ hybridization and immunohistochemistry. Mononuclear cells expressing IFN-gamma and IL-4 mRNA were aggregated in inflamed portal tracts in PBC livers, but were rarely present in extrahepatic biliary obstruction, alcoholic fibrosis, or normal liver sections. The IFN-gamma and IL-4 mRNA positive cells in PBC livers were detected in significantly higher numbers than in control livers (P < .01). Moreover, IFN-gamma mRNA expression was more commonly detected than IL-4 expression in PBC livers, and the levels of IFN-gamma mRNA expression were highly correlated with the degree of portal inflammatory activity. IFN-gamma mRNA-positive cells were detected primarily around damaged bile ducts that were surrounded by lymphoid aggregates. The data indicate that Th1 cells are the more prominent T-cell subset in the lymphoid infiltrates in PBC.

Actins↗

PubMed1992

Interconversion of three differentially modified and assembled forms of BiP.

The immunoglobulin heavy chain binding protein BiP/GRP78 is post-translationally modified by phosphorylation and ADP ribosylation. In cells induced to synthesize higher levels of BiP, either due to the accumulation of nontransported proteins or to glucose starvation, both BiP phosphorylation and ADP ribosylation are reduced. BiP bound to other proteins is unmodified, suggesting that both phosphorylation and ADP ribosylation are restricted to the unbound BiP pool. In the present study, both modifications were further characterized in terms of their stability, the pool of BiP that harbored these modifications, and the relationship between the modified and unmodified forms of BiP. While levels of BiP synthesis vary according to the physiological state of a cell, we found that both induced and uninduced cells contain similar amounts of free BiP. However, free BiP in uninduced cells was found primarily in an aggregated state, whereas in cells that accumulate nontransported proteins, it was predominantly monomeric. Both phosphorylation and ADP ribosylation were restricted to the aggregated form of free BiP. These post-translational modifications occurred upon release of BiP from associated proteins, and could be reversed upon induction of BiP synthesis. Therefore, BiP exists either (1) complexed to other proteins, (2) as a free unmodified monomer, or (3) as free modified aggregates. Our data suggest that BiP can be interconverted from one state to another, and that the various forms are functionally distinct.

Adenosine Diphosphate↗

PubMed2002

The reliability of the Massachusetts Substance Abuse Management Information System.

State substance abuse management information systems increasingly are becoming important tools for research, program management, and policy formulation at federal and state levels. These systems are currently undergoing radical expansion, leading to the creation of statewide performance and outcome monitoring systems for publicly-funded substance abuse treatment. This expansion makes imperative increased knowledge of the psychometric properties of the data in these systems. This study develops a method for examining the reliability of such data and applies it to the Massachusetts Substance Abuse Management Information System (SAMIS). Cohen's kappa, intraclass correlations, and the techniques of Heise (1969) are used to assess the reliability of different types of variables. Results show that key variables on the SAMIS Admission Form exhibit moderate to high reliability, supporting the use of this data for aggregate analyses. At the same time, caution should be used in making judgments about individual patients.

Adult↗

PubMed2005

In praise of clinical judgment: Meehl's forgotten legacy.

Although Paul E. Meehl demonstrated the limits of informal aggregation of data and prognostication by presumed experts, he remained convinced that clinical experience confers expertise of some kind. The authors explore this forgotten side of Meehl's legacy by reconsidering the validity of clinical judgment in its natural context, everyday clinical work. Three domains central to clinical practice are examined: diagnosis, interpretation of meaning, and intervention. It is argued that a more sanguine picture of clinical expertise emerges when the focus shifts from prediction at high levels of inference to (a) judgments at a moderate level of inference, (b) contexts for which clinical training and experience are likely to confer expertise, and (c) conditions that optimize the expression of that expertise (e.g., use of instruments designed for expert observers). The authors conclude by examining domains in which clinical judgment could prove useful in knowledge generation (e.g., hypothesis generation, identification of falsifying instances, item development).

Clinical Competence↗

PubMed1993

Current management of varicella zoster virus infections.

A series of randomized, placebo-controlled, double-blind clinical trials conducted from 1980 to the present provide the basis for appropriate management of varicella-zoster virus (VZV) infections. Placebo recipients in these studies have also provided valuable natural history data on the clinical course of VZV infections. The protocols in toto have shown acyclovir (ACV) to be safe and effective for treatment of nearly all forms of acute VZV infection. A number of issues still need to be addressed, including appropriate dosage, importance of early initiation of therapy, cost-benefit ratio, and viral resistance. Considering the data in aggregate, the author recommends ACV treatment for all acute VZV infections in immunocompromised hosts; for acute herpes zoster infections in all adults; and for varicella in otherwise healthy adults and adolescents, and children who contract it from a sibling.

Acyclovir↗

PubMed1995

Altered expression and function of E-cadherin in cervical intraepithelial neoplasia and invasive squamous cell carcinoma.

HECD-1 monoclonal antibody has been used to localize E-cadherin, a calcium-dependent cell-cell adhesion molecule, in microwave-treated, paraffin-embedded sections from 53 cases of cervical intraepithelial neoplasia (CIN) (11 CIN I, 22 CIN II, and 20 CIN III), 16 invasive cervical squamous cell carcinomas, and seven metastases. In normal cervix, E-cadherin was expressed on the cell membrane of basal and parabasal cells. Cytoplasmic staining was present in occasional basal cells only. In CIN, the presence and localization of cytoplasmic E-cadherin were found to be significantly correlated with the grade of the CIN lesion. In squamous cell carcinomas, reduced membranous and increased cytoplasmic staining was seen with worsening differentiation. Loss of membranous E-cadherin expression was also detected in 4/7 metastatic deposits. E-cadherin expression (120 kD form on Western blotting) was seen in human cervical carcinoma cell lines (HT3, ME180, C4I, Caski) that maintained the ability to aggregate in a homotypic adhesion assay and showed a typical epithelial morphology. E-cadherin-negative cell lines (Hela, SiHa, C33A) did not show adhesion. HOG-1 was the only E-cadherin-negative cell line which showed a significant degree of cell-cell aggregation. These data indicate that loss of membranous E-cadherin expression may represent one of the abnormalities underlying loss of cell polarity and differentiation which characterize CIN and invasive cervical cancer.

Blotting, Western↗

PubMed2006

Epidemiological evaluation of intraoperative antibiosis as a protective agent against endophthalmitis after cataract surgery.

PURPOSE: To evaluate risk factors for endophthalmitis after cataract surgery and to retest recent findings on the protective effect of intraoperative antibiosis and the promoting effect of the clear corneal as compared to sclerocorneal incision. DESIGN: Survey study. PARTICIPANTS: Five hundred thirty-eight ophthalmosurgical centers in Germany. MAIN OUTCOME MEASURE: Responder specific endophthalmitis incidence. RESULTS: A total of 310 (58%) questionnaires were computed resulting in an overall count of 404 356 cataract surgeries and 291 self-reported endophthalmitis cases (crude rate 0.072%). The risk of postoperative endophthalmitis for sclerocorneal versus clear corneal incisions was not significantly reduced (relative risk 0.97, 99% confidence interval 0.69-1.38). The hypothesis of a protective effect of intraocular antibiosis could be confirmed by a significantly decreased risk ratio of 0.69 (99% confidence interval 0.48-0.99) indicating a significant benefit from intraoperative intraocular antibiosis. A similar tendency was observed for an intraoperative periocular antibiosis with a significantly reduced risk ratio of 0.68 (99% confidence interval 0.49-0.96). These risk estimates had been adjusted for the size of the surgical center: a significantly reduced risk ratio of 0.70 (99% confidence interval 0.49-0.98) for postoperative endophthalmitis was observed for local centers. CONCLUSIONS: Whereas this 2001 appraisal of a survey in 1996 could not reproduce the benefit of sclerocorneal incision, the protective effect of intraoperative intraocular antibiotic prophylaxis could be confirmed. However, the results of this survey have to be interpreted with care, since it is not based on individual case information, but rather on aggregate questionnaire data.

Antibiotic Prophylaxis↗

PubMed2001

Construction of a single global scale for multi-item assessments of the same variable.

Complex health-related concepts are commonly measured by means of multi-item scales or questionnaires. As the item scales of an instrument cover different aspects of the same variable, a single global response value is required of the concept to be measured. In this paper, different approaches that take into account the non-metric properties of ordered categorical data when aggregating multi-item scales into global scaling were suggested. A single score of equally important items is easily defined by the median. When the multi-items are constructed to identify the most serious sign of a particular state, the maximum categorical level of the items could be an appropriate single score of the variable. By means of the joint response scheme over two aspects of the same variable, a global scale with an optional number of ordered categories could be defined. Some of the multi-item scales of the Short-Form Health Survey (SF-36) and Euro-QoL were used for illustrations to the proposed approaches.

Health Surveys↗

PubMed2002

Adjustment for misclassification in studies of familial aggregation of disease using routine register data.

This paper discusses the misclassification that occurs when relying solely on routine register data in family studies of disease clustering. A register study of familial aggregation of schizophrenia is used as an example. The familial aggregation is studied using a regression model for the disease in the child including the disease status of the parents as a risk factor. If all the information is found in the routine registers then the disease status of the parents is only known from the time when the register started and if this information is used unquestioningly the parents who have had the disease before this time are misclassified as disease-free. Two methods are presented to adjust for this misclassification: regression calibration and an EM-type algorithm. These methods are used in the schizophrenia example where the large effect of having a schizophrenic mother hardly shows any signs of bias due to misclassification. The methods are also studied in simulations showing that the misclassification problem increases with the disease frequency.

Adolescent↗

PubMed1995

Decreased m3-muscarinic and alpha 1-adrenergic receptor stimulation of PIP2 hydrolysis in parotid gland membranes from aged rats: defect in activation of G alpha q/11.

m3-Muscarinic cholinergic receptor (m3-AChR) and alpha 1-adrenergic receptor (alpha 1-AR) stimulation of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis (by a PIP2-specific phospholipase C, PLC) in rat parotid gland membranes is mediated via activation of alpha subunits of the Gq/11 family of G-proteins. This study examines m3-AChR and alpha 1-AR stimulation of PIP2 hydrolysis in membranes isolated from parotid glands of old (24 months) and young (3 months) rats (old and young rat membranes). Old rat membranes exhibited reduced stimulation of PIP2 hydrolysis in response to the addition of guanosine-5'-O-(3-thiotrisphosphate) (GTP gamma S) alone or GTP gamma S plus either carbachol (m3-AChR agonist) or epinephrine (alpha 1-AR agonist). This reduction in receptor-stimulated PIP2 hydrolysis was not due to a decrease in PLC activity per se since cholate-solubilized PLC activity was similar in old and young rat membranes. Additionally, these membranes exhibited comparable, immunologically detectable, levels of PLC beta 3, G alpha q/11, and G beta. In the presence of 10 microM AlCl3 and 10 mM NaF, stimulation of PIP2 hydrolysis in both old and young rat membranes was similar. Preincubation of membranes from old rats with GTP gamma S induced a time-dependent increase in the rate of PIP2 hydrolysis and, with 20 min preincubation, the rates of hydrolysis in old and young rat membranes were not statistically different. In aggregate, these data indicate that there is a defect in the activation of G alpha q/11 in parotid gland membranes from old rats.

Adenylyl Cyclases↗

PubMed1997

Uncoupling of S-phase and mitosis by recombinant cytotoxic necrotizing factor 2 (CNF2).

Cytotoxic necrotizing factor 2 (CNF2) is an exotoxin identified from virulent clinical isolates of Escherichia coli. It has been characterized in adherent cell lines as an inducer of cellular death, hyperploidy (multinucleation), and cytoskeletal reorganization. The molecular mechanism of these actions is unclear. Two cellular mechanisms can be hypothesized to explain the DNA content increase (hyperploidy) induced by the toxin. The first is that the toxin interferes with cytoplasmic division without interfering with normal nuclear cycling, such that DNA is replicated in the absence of cell division. The second is that the toxin drives the nuclear machinery to replicate the DNA multiple times within one cell cycle, without interfering with cytoplasmic division. In order to investigate these phenomena, we have constructed a recombinant CNF2 gene that expresses a toxin with both an epitope tag and a polyhistidine tag. Extracts made from E. coli that express this gene have a high multinucleating activity that colocalizes with the recombinant 115-kDa protein. To distinguish between these hypotheses, we used recombinant CNF2 and several growth conditions (time, partial differentiation, and stage of growth) to establish a relationship between cellular divisions and generation of hyperploidy. It was also determined that the toxin had no effect upon in vitro DNA replication using a Xenopus egg extract system. In aggregate, these data are consistent with the hypothesis that CNF2 is affecting cytoplasmic division and thereby removing the requirement for a completed mitosis before the initiation of another S-phase. These data are discussed in relation to the generation of polyploid cells during megakaryopoeisis and the generation of aneuploid cells during tumorigenesis.

3T3 Cells↗

PubMed2002

Interactions between a nonionic gemini surfactant and cyclodextrins investigated by small-angle neutron scattering.

The microstructure of complexes between hydroxypropyl-cyclodextrins (HPCDs) (alpha, beta, and gamma) and a novel gemini surfactant has been investigated by small-angle neutron scattering (SANS). This nonionic hetero-gemini surfactant (denoted NIHG750) contains two hydrophobic groups and two hydrophilic groups. One is a methyl-capped polyoxyethylene chain with 16 oxyethylene units and the other is a secondary hydroxyl group. Various form factor models have been considered for fitting the SANS data. Spherical aggregates (25 to 40 A) with a size slightly larger than that of NIHG750 micelles (about 23 A) appear in mixed systems. These could be micellar aggregates partly covered with a few cyclodextrin molecules. In addition, the results indicate rod formation (r approximately 8 A, L approximately 70 A) for the NIHG-HPCD complexes. This result is consistent with the threading of HPCDs onto NIHG750 to such an extent that the surfactant molecule takes an extended conformation at high levels of HPCD. Also, the results indicate that HPCDs may interact with the oxyethylene groups of the spherical micellar aggregates leading to an increase in micelle size and a gradual transformation to rod-shaped aggregates. The tendency to form rods increases in the order gamma-CD<alpha-CD<beta-CD. An increase in HPCD concentration results in an increased amount of rods in the system. All spherical aggregates disappear at relative amounts of HPbetaCD above 4 to 5 (molar ratio). However, for HPalphaCD and HPgammaCD spherical aggregates coexist with rod shaped aggregates in the whole range of concentrations investigated here.

Cyclodextrins↗