Bias in treatment assignment in controlled clinical trials

Controlled clinical trials of the treatment of acute myocardial infarction offer a unique opportunity for the study of the potential influence on outcome of bias in treatment assignment. A group of 145 papers was divided into those in which the randomization process was blinded (57 papers), those in which it may have been unblinded (45 papers), and those in which the controls were selected by a nonrandom process (43 papers). At least one prognostic variable was maldistributed (P less than 0.05) in 14.0 per cent of the blinded-randomization studies, in 26.7 per cent of the unblinded-randomization studies, and in 58.1 per cent of the nonrandomized studies. Differences in case-fatality rates between treatment and control groups (P less than 0.05) were found in 8.8 per cent of the blinded-randomization studies, 24.4 per cent of the unblinded-randomization studies, and 58.1 per cent of the nonrandomized studies. These data emphasize the importance of keeping those who recruit patients for clinical trials from suspecting which treatment will be assigned to the patient under consideration.     

Multiple signals regulate the intracellular trafficking of HLA-DM in B-lymphoblastoid cells.

Peptide loading by major histocompatibility complex (MHC) class II molecules occurs in the endocytic pathway and is critically dependent upon the function of the class II-related molecule human leucocyte antigen-DM (HLA-DM). We have previously shown that a tyrosine-based lysosomal targeting signal present in the cytoplasmic tail of DMB has the capacity to target HLA-DM to peptide-loading compartments in HeLa cells. Here we investigate the importance of this signal in directing HLA-DM to processing compartments in professional antigen-presenting cells. We reconstituted a DMB-negative B-lymphoblastoid cell line with native or targeting-deficient DMB and show that in the absence of its tyrosine signal, DMB-Y230A is as efficient as the wild-type molecule in inducing MHC class II SDS stable dimer formation; restoring expression of the conformation-dependent DR3 epitope 16:23; the removal of CLIP; and accessing lysosomal peptide-loading compartments. By transient transfection in HeLa cells we show that Ii is able to compensate for loss of DMB-encoded targeting information. These data imply that in cells expressing physiological levels of class II, Ii and DM, there is sufficient association with Ii to direct the majority of DM into the endocytic pathway. Thus MHC class II and HLA-DM may follow similar intracellular trafficking pathways on route to antigen-processing compartments.     

Comparison of methods for identifying resistant herpes simplex virus and measuring antiviral susceptibility.

BACKGROUND: A number of in vitro assays are used to determine susceptibility of HSV to antiviral agents, but results from these in vitro assays do not necessarily correlate with treatment outcome. OBJECTIVES: A method with improved capability for identifying an isolate as acyclovir (ACV) or penciclovir (PCV) resistant when resistance is borderline could greatly improve the management of HSV disease. STUDY DESIGN: A comparative evaluation of four in vitro assays, plaque reduction (PRA), DNA hybridization, plating efficiency (PEA) and plaque autoradiography (PAR) was performed to accurately identify and measure resistance of a TK-altered clinical HSV isolate (HSV-1 N4) from a patient who was non-responsive to ACV treatment. Two established criteria for the prediction of antiviral resistance, IC(50)> or =2.0 microg/ml or an IC(50) greater than 10x above a sensitive virus IC(50), as well as testing in human (MRC-5) and nonhuman (Vero and CV-1 monkey kidney) cell lines were evaluated. RESULTS: The PRA and DNA hybridization assays accurately identified HSV-1 N4 as ACV(r) in human cells when using the 10x above sensitive virus IC(50) resistance criterion. Moreover, the PEA and PAR assays failed to classify HSV-1 N4 as drug resistant and indicate that these technologies alone are inadequate for identifying resistant virus. CONCLUSIONS: The data presented herein indicate that the PRA and DNA hybridization assays most accurately identified an otherwise borderline-resistant isolate as drug resistant: (i) when a sensitive virus is used within each individual assay as a control, (ii) when ACV and PCV susceptibility is evaluated in human cells, and (iii) when the 10x above sensitive IC(50) criterion is used to classify a virus as drug-resistant. Testing of additional clinical samples is warranted to further confirm these findings.     

Chronic dermal sinuses as a manifestation of histiocytosis X

Two young patients presented with generalised lymphadenopathy, otorrhoea, otitis, and rash. Over the next few years chronically discharging sinuses began to form over enlarged nodes and histological appearances were typical of histiocytosis X. In neither case were micro-organisms isolated from the lesions, and in both patients healing occurred with immunosuppressive agents. Chronic dermal sinus formation secondary to lymph node disease has never before been recorded as a manifestation of histiocytosis X. Histiocytosis X should therefore be considered in the differential diagnosis of "suppurative" lymphadenopathy so that appropriate treatment may be given without delay.     

Nonfatal physical violence, United States, 1994.

OBJECTIVES: Most surveillance and research efforts focus on severe violence, especially on homicides. Because less extreme forms of violence may be precursors to more extreme forms, the authors analyzed data from a national survey to describe the extent of nonfatal physical violence in the US. METHODS: The authors generated weighted national estimates from responses to a random-digit-dialed telephone survey. Respondents were asked if they had been "hit, slapped, pushed, or kicked by another person or hit with an object or weapon" in the preceding 12 months. Respondents were also asked how many times such incidents had occurred and, for the last such episode, their relationship with the perpetrator, whether they had been injured, and, if so, whether they had sought medical treatment. RESULTS: The authors estimate that approximately 15 million people, or 8% of the US adult population, experienced nonfatal physical violence, as defined for this study, during a 12-month period. Male gender, the 18-24-year-old age group, never having been married, being out of work or a student, and heavy drinking were associated with a higher likelihood of being assaulted. An estimated 75% of assaults were by a known person and 26% by a stranger. Women were more likely than men to be assaulted by current or former intimate partners; men were more likely than women to be assaulted by strangers. An estimated 18% of incidents resulted in injuries, and an estimated 7% required medical attention. CONCLUSIONS: Nonfatal physical violence is fairly common in the US and may lead to more than one million medical encounters each year.     

Beyond our borders

People living with HIV and AIDS face medical, social, and political challenges all over the world. The HIV and AIDS pandemic strikes less developed countries to such a degree that the reports of HIV-positive populations are unfathomable to our Western urban society. Thailand is spotlighted as one of these countries where AZT access is virtually unattainable and "new drugs" are not even an option. Alternative herbal "medicines" are the only therapy available to most Asians. India, which seems to be receiving the attention and funding that Thailand recently lost, is among other countries spotlighted. India began receiving international AIDS money when then Prime Minister Atal Vajpayee admitted in 1998 that the country had a massive AIDS problem. This money, however, is restricted, leaving local ASOs unable to fund basic needs. New approaches to funding are being implemented and international support is needed to combat the chronic lack of resources.     

Modified therapeutic community for mentally ill chemical abusers: outcomes and costs.

Several studies have established that the personal and social consequences of substance abuse are extensive and costly. These consequences are frequently compounded by mental illness. Although interventions that target mentally ill chemical abusers (MICAs) present several challenges, the potential benefits of successful interventions are significant. This article presents outcomes and costs of a modified therapeutic community (TC) intervention for homeless MICAs. Outcomes at follow-up are compared with those for a control group of homeless MICAs receiving standard services in a "treatment-as-usual" (TAU) condition. Annual economic costs for the modified TC and the average weekly cost of treating a single client are estimated. Treatment and other health service costs at 12 months postbaseline are compared for modified TC and TAU clients. The results of this study indicate that, suitably modified, the TC approach is an effective treatment alternative for homeless MICAs, with the potential to be highly cost-effective relative to standard services.     

Cell, tissue and organ culture as in vitro models to study the biology of squamous cell carcinomas of the head and neck

In vitro models are currently being used to study head and neck squamous cell carcinoma (HNSCC). Several hundred HNSCC cell lines have been established by various investigators and used to study a broad spectrum of questions related to head and neck cancer. The head and neck model with respect to multistage carcinogenesis is now complete. Several techniques exist for the culture of normal epithelial cells from the upper aerodigestive tract (UADT). The biology of these UADT cells (oral cavity, oropharynx, hypopharynx and larynx) is being studied. Successful culture of premalignant lesions (dysplastic mucosa, leukoplakia, erythroplakia) has resulted in establishment of a limited number of premalignant cell lines and cell cultures. HPV infection of normal oral epithelial cells for immortalization ( premalignant cells) coupled with transformation with carcinogens (malignant cells) has established an experimental model for progression. Two in vivo models for oral carcinogenesis, the 7,12 dimethylbenz(a)anthracene-induced hamster cheek pouch model and the 4-nitroquinoline-N-oxide rat oral model, have been established in culture. Thus, multistage carcinogenesis models have been established from both human tissues and animal models and include cultures of normal, premalignant and malignant cells. Culture techniques for growing dissociated primary tumor cells for short term experimental analysis are being used. The culture of normal or tumor tissue as organ/explant cultures allows for the maintenance of normal cell-cell and cell-matrix interactions, but limits experimentation since these cultures cannot be propagated. Several three dimensional model systems are being used to obtain this histological complexity but allow for experimentation. The ability to culture normal, premalignant and malignant cells coupled with the use of a variety of culture techniques, should allow for the continued growth and experimentation in head and neck cancer research.