Exploring an alternative approach to Lyme disease surveillance in Maryland.

In Maryland, Lyme disease (LD) is a reportable disease and all laboratories and healthcare providers are required to report to the local health department. Given the volume of LD reports and effort required for investigation, surveillance for LD is burdensome and subject to underreporting. We explored the utility of International Classification of Diseases, 9th Revision, Clinical Modification (administrative) codes for use with LD surveillance. We aimed to collect the administrative codes for a 10% sample of 2009 LD reports (n = 474) from 292 facilities stratified by case classification (confirmed, probable, suspected and not a case). Sixty-three per cent (n = 184) of facilities responded to the survey, and 341 different administrative codes were obtained for 91% (n = 430) of sampled reports. The administrative code for Lyme disease (088.81) was the most commonly reported code (133/430 patients) among sampled reports; while it was used for 62 of 151 (41%) confirmed cases, it was also used for 48 of 192 (25%) not a case reports (sensitivity 41% and specificity 73%). A combination of nine codes was developed with sensitivity of 74% and specificity of 37% when compared to not a case reports. We conclude that the administrative code for LD alone has low ability to identify LD cases in Maryland. Grouping certain codes improved sensitivity, but our results indicate that administrative codes alone are not a viable surveillance alternative for a disease with complex manifestations such as LD.

Assessing diagnostic coding practices among a sample of healthcare facilities in Lyme disease endemic areas: Maryland and New York - A Brief Report.

The value of using diagnostic codes in Lyme disease (LD) surveillance in highly endemic states has not been well studied. Surveys of healthcare facilities in Maryland (MD) and New York (NY) regarding coding practices were conducted to evaluate the feasibility of using diagnostic codes as a potential method for LD surveillance. Most respondents indicated that their practice utilized electronic medical records (53%) and processed medical/billing claims electronically (74%). Most facilities were able to search office visits associated with specific ICD-9-CM and CPT codes (74% and 73%, respectively); no discernible differences existed between the healthcare facilities in both states. These codes were most commonly assigned by the practitioner (82%), and approximately 70% of respondents indicated that these codes were later validated by administrative staff. These results provide evidence for the possibility of using diagnostic codes in LD surveillance. However, the utility of these codes as an alternative to traditional LD surveillance requires further evaluation.

Characterizing Lyme Disease Surveillance in an Endemic State.

Lyme disease (LD) is the most common vector-borne disease in Maryland and the United States. Surveillance for LD is valuable for understanding the burden of the disease, particularly to assess whether the disease is spreading and to appreciate who is affected. However, not all cases of LD in Maryland are reported, and surveillance practices vary across each of Maryland's 24 local health departments (LHDs). To better understand this variability and to systematically characterize the surveillance process, we surveyed Maryland's LHDs regarding LD surveillance. The Maryland Local Health Department Lyme Disease Surveillance Survey has been administered annually since 2011. Questions asked each year included whether all LD reports are investigated or only a subset, and how many reports are not entered into the surveillance database. Since 2011, Maryland has lost surveillance personnel for LD. Each year from 2009 to 2012, a median 3598 (range 2462 to 5722) reports were not entered into the surveillance database and hence not investigated. These reports represent 43-55% of all reports received for the year. Over time, more LHDs chose to streamline their LD investigation approach by investigating only those reports that met the criteria for laboratory evidence of infection: in 2008, 5 (21%) LHDs investigated only a subset of LD reports; by 2013, this increased to 15 (63%). There is wide variability across LHDs in how LD investigations are conducted. Maryland LHDs have experienced a loss of LD surveillance personnel with a concomitant increase in the number of LHDs adopting a streamlined approach to investigating cases. These findings underscore the tremendous burden of LD on the public health agencies and highlight the need for alternative approaches that can both reduce burden and preserve surveillance data quality.

Cognitive ability is associated with altered medial frontal cortical circuits in the LgDel mouse model of 22q11.2DS.

We established a relationship between cognitive deficits and cortical circuits in the LgDel model of 22q11 Deletion Syndrome (22q11DS)-a genetic syndrome with one of the most significant risks for schizophrenia and autism. In the LgDel mouse, optimal acquisition, execution, and reversal of a visually guided discrimination task, comparable to executive function tasks in primates including humans, are compromised; however, there is significant individual variation in degree of impairment. The task relies critically on the integrity of circuits in medial anterior frontal cortical regions. Accordingly, we analyzed neuronal changes that reflect previously defined 22q11DS-related alterations of cortical development in the medial anterior frontal cortex of the behaviorally characterized LgDel mice. Interneuron placement, synapse distribution, and projection neuron frequency are altered in this region. The magnitude of one of these changes, layer 2/3 projection neuron frequency, is a robust predictor of behavioral performance: it is substantially and selectively lower in animals with the most significant behavioral deficits. These results parallel correlations of volume reduction and altered connectivity in comparable cortical regions with diminished executive function in 22q11DS patients. Apparently, 22q11 deletion alters behaviorally relevant circuits in a distinct cortical region that are essential for cognitive function.

First spinal axis segment irradiation with spot-scanning proton beam delivered in the treatment of a lumbar primitive neuroectodermal tumour. Case report and review of the literature.

Primary intraspinal primitive neuroectodermal tumour (PNET) is a rare tumour entity. The optimal therapeutic management is unclear but, in general, this tumour is treated with surgery followed by radiotherapy and chemotherapy. Proton beam radiation therapy (PT) offers superior dose distributional qualities compared with X- or gamma rays, as the dose deposition occurs in a modulated narrow zone called the Bragg peak. As a result, organs at risk are optimally speared. Here, we present a patient treated with the first spinal axis segment irradiation using spot-scanning PT with a single field, combined with conventional cranio-spinal axis radiotherapy after surgery and chemotherapy, and an extensive review of the literature outlining the clinical features and treatment modality of spinal PNET.

Evaluation of an extensive tuberculosis contact investigation in an urban community and jail.

SETTING: Urban community and jail. OBJECTIVES/DESIGN: Evaluate outcome and process of an extensive tuberculosis contact investigation, including completion of treatment of latent TB infection (TLTBI). RESULTS: Between April 2000 and September 2001, 18 epidemiologically-linked tuberculosis cases were identified; 15 were culture-confirmed, all with a matching 14-band DNA fingerprint pattern. The source case had cavitary pulmonary disease and had been incarcerated 4 months prior to diagnosis. Sixty-six of 67 (99%) community contacts and 221/344 (64%) jail contacts were evaluated. The presumed new infection rate was 56% for community contacts (11 cases, 25 tuberculin skin test [TST] positive) and 20% for jail contacts (6 cases, 32 TST converters). Screening results for 113 (33%) jail contacts were obtained in the jail TST registry upon rearrest. All identified cases completed treatment. Of 22 community contacts initiating TLTBI, 11 completed (44% of infected, 50% of initiators). Of 32 infected jail contacts, 12 initiated TLTBI (all who remained incarcerated), and 10 completed (31% of infected, 83% of initiators). None of 20 additional in-fected jail contacts, all of whose TST conversions were identified with re-arrest data, were subsequently located. Two additional related cases have been identified as of October 2003. CONCLUSIONS: Close health department/corrections collaboration facilitated this extensive contact investigation, which identified high Mycobacterium tuberculosis transmission rates and controlled the outbreak. Numerous contacts were identified and screened, but rates of treatment completion for infected contacts were low. Novel strategies are needed to maximize the number of infected contacts who are not only identified and evaluated, but completely treated.

Altered apoptotic profiles in irradiated patients with increased toxicity.

PURPOSE: A retrospective study of radiation-induced apoptosis in CD4 and CD8 T-lymphocytes, from 12 cancer patients who displayed enhanced toxicity to radiation therapy and 9 ataxia telangiectasia patients, was performed to test for altered response compared to healthy blood-donors and normal cancer patients. METHODS AND MATERIALS: Three milliliters of heparinized blood from each donor was sent via express post to the Paul Scherrer Institute (PSI) for subsequent examination. The blood was diluted 1:10 in RPMI medium, irradiated with 0-, 2-, or 9-Gy X-rays, and incubated for 48 h. CD4 and CD8 T-lymphocytes were then labeled using FITC-conjugated antibodies, erythrocytes were lysed, and the DNA stained with propidium iodide. Subsequently, cells were analyzed using a Becton Dickinson FACScan flow cytometer. Radiation-induced apoptosis was recognized in leukocytes as reduced DNA content attributed to apoptosis-associated changes in chromatin structure. Apoptosis was confirmed by light microscopy, electron microscopy, and by the use of commercially available apoptosis detection kits (in situ nick translation and Annexin V). Data from hypersensitive individuals were compared to a standard database of 105 healthy blood-donors, and a database of 48 cancer patient blood donors who displayed normal toxicity to radiation therapy. To integrate radiosensitivity results from CD4 and CD8 T-lymphocytes after 2 and 9 Gy, z-score analyses were performed. RESULTS: A cohort of 12 hypersensitive patients was evaluated; 8 showed enhanced early toxicity, 3 showed enhanced late toxicity, and 1 showed both. The cohort displayed less radiation-induced apoptosis (-1.8 sigma) than average age-matched donors. A cohort of 9 ataxia telangiectasia homozygotes displayed even less apoptosis (-3.6 sigma). CONCLUSION: The leukocyte apoptosis assay appears to be a useful predictor of individuals likely to display increased toxicity to radiation therapy; however, validation of this requires a prospective study.

Dexamethasone-induced enhancement of resistance to ionizing radiation and chemotherapeutic agents in human tumor cells.

BACKGROUND: Dexamethasone-induced changes in radioresistance have previously been observed by several authors. Here, we examined effects of dexamethasone on resistance to ionizing radiation in 10 additional human cell lines and strains, and on resistance to carboplatin and paclitaxel in 13 fresh tumor samples. MATERIAL AND METHODS: Eight human carcinoma cell lines, a glioblastoma cell line and a strain of normal human diploid fibroblasts were arbitrarily chosen for these in-vitro studies. Effects on radiosensitivity were assessed using a conventional colony formation assay. Effects on resistance to the drugs were investigated prospectively (ATP cell viability assay) using 13 fresh tumor samples from consecutive patients operated for ovarian cancer within the context of a Swiss nation-wide randomized prospective clinical trial (SAKK 45/94). RESULTS: Dexamethasone promoted proliferation of 1 of the cell lines without affecting radiosensitivity, while it completely inhibited proliferation of another cell line (effects on radiosensitivity could thus not be examined). Furthermore, dexamethasone induced enhanced radioresistance in 1 of the 8 carcinoma cell lines examined. In the glioblastoma cell line, there was no effect on growth or radioresistance, nor in the fibroblasts. Treatment with dexamethasone enhanced resistance of the malignant cells to carboplatin in 4 of the 13 fresh tumor samples examined, while no enhancement in resistance to paclitaxel was observed. CONCLUSIONS: In agreement with previous reports, we found that dexamethasone may induce radioresistance in human carcinoma cells. Including the published data from the literature, dexamethasone induced enhancement in radioresistance in 4 of 12 carcinoma cell lines (33%), but not in 3 glioblastoma cell lines, nor in 3 fibroblast strains. Dexamethasone also induced enhanced resistance to carboplatin with a similar probability in fresh samples of ovarian cancer evaluated prospectively (in 4 of 13 samples; 31%). We worry that induction of resistance by corticosteroids given to patients undergoing either radiotherapy or chemotherapy with agents causing DNA damage might be associated with a reduced clinical responsiveness in a significant fraction of patients with a carcinoma.

A biophysical basis of enhanced interstitial fluid pressure in tumors.

It is widely accepted that enhanced interstitial fluid pressure (IFP) in tumors is a major obstacle against delivery of therapeutic agents. On the other hand, the origin of enhanced IFP remains controversial. Here, the Van't Hoff equation is applied to examine how glucose breakdown to CO2 and lactate in tumor cells may affect intracellular osmotic pressure. According to the equation, it is found that production of CO2 from glucose lowers osmotic pressure inside cells, while glycolytic production of lactate generates significant increases. Crucial to a net enhancement of pressure in cells is the Warburg ratio, the ratio of the fraction of glucose transformed to lactate divided by the fraction of glucose metabolized to CO2: if (and only if) the ratio is higher than 1.0, there is a resulting increase in intracellular osmotic pressure. Under fully anaerobic glycolysis, the enhancement of intracellular pressure is maximal, namely 19.3 mmHg per mM of glucose metabolized to lactate (Van't Hoff equation). Cells are then biological pressure pumps driven by glycolytic production of lactate, causing IFP to raise. It is proposed that a regulatory feedback loop prevents IFP to raise above microvascular pressure (MVP). Accordingly, enhanced IFP in tumors is the result of high rates of tumor glycolysis, and enhancement of IFP is limited by MVP. It is thus concluded that a high rate of glycolytic production of lactate in tumor cells ultimately prevents both access of therapeutic agents to the malignant cells and immunological surveillance, and that it indirectly drives outward currents of interstitial fluid, thereby propelling both the process of tumor infiltration of surrounding structures and metastatic spread, depending on deformability and proteolytic capacity of the malignant cells.

Dexamethasone-induced radioresistance occurring independent of human papilloma virus gene expression in cervical carcinoma cells.

BACKGROUND: Inactivation of p53 by binding to simian virus 40-T antigen (SV40-T) and human papilloma virus type 16 protein E6 (HPV 16 E6) in transfected human diploid fibroblasts causes enhanced radioresistance. The aim of this study was to investigate the role of HPV 18 E6 and E7 gene products with respect to radiosensitivity of two cervical carcinoma cell lines. MATERIALS AND METHODS: The two cervical carcinoma lines C4-1 and SW 756 were used in which treatment with dexamethasone allows to modulate expression levels of HPV 18 E6 and E7 genes: upregulation in C4-1, downregulation in SW 756. Effects of treatment with dexamethasone on plating efficiency and radiosensitivity were assessed using a clonogenic assay. RESULTS: Treatment with dexamethasone increased plating efficiency of the C4-1 cells, but did not affect plating efficiency of SW 756 cells. Treatment with dexamethasone induced enhanced radioresistance in both cell lines. Thus in C4-1 cells the observed changes in radioresistance correlate to the enhancement in expression of HPV 18 genes E6/E7, whereas in SW 756, a reduced expression correlates negatively with the enhanced radioresistance. CONCLUSIONS: In C4-1 and SW 756 cells, treatment with dexamethasone induces radioresistance, and changes in expression levels of HPV 18 genes E6 and E7 do not correlate with the changes in radiosensitivity. Dexamethasone-induced radioresistance has previously been observed in HeLa cells, another human cervical carcinoma cell line. This leads us to speculate that dexamethasone-induced radioresistance may be important in certain clinical situations, and that therefore, the phenomenon deserves further study.

Prognostic factors associated with loss of heterozygosity at the RB1 locus in retinoblastoma.

The nature of the tumorigenic mutation was analyzed in 30 retinoblastoma (Rb) tumors (16 non-hereditary and 14 hereditary) and categorized into loss of heterozygosity (LOH) or retention of heterozygosity (non-LOH) at the RB1 locus. These genotypic characteristics were compared with the clinicopathological phenotype for possible correlation. The overall frequency of LOH was roughly 55%, in both hereditary and non-hereditary Rb. The presence of LOH was preferentially associated with differentiated tumors and absence of choroidal invasion. LOH was found in 82% of females versus 33% of males. Finally, LOH-initiated tumors were associated with a significantly younger age at diagnosis in hereditary Rb. In conclusion, the preferential association of LOH with absence of choroidal invasion, tumoral differentiation, and younger age at diagnosis may establish LOH as a prognostic marker in Rb patients.

Exogenous lactate interferes with cell-cycle control in Balb/3T3 mouse fibroblasts.

PURPOSE: Previous studies have shown that exogenous lactate may influence proliferation rates, radiation sensitivity, and postirradiation repair capacity of mammalian cells. In the present study, we addressed the question of potential underlying mechanisms and, therefore, examined effects of exogenous lactate on proliferation rates and cell-cycle distribution in immortal but nontumorigenic mammalian cells. METHODS AND MATERIALS: Cells were grown at 37 degrees C in an incubator with 5% CO2 and 95% air, in a culture medium supplemented or not with lactate at a 10 mM concentration. Daily, we changed the culture medium and counted cells per dish. On selected days, cell-cycle distribution was determined by flow cytometry. Balb/3T3 mouse fibroblasts were used. RESULTS: During the exponential phase of cell proliferation, mean population doubling time was significantly increased from 17.7 to 19.9 h, due to selective prolongation of G2/M. However, in density-inhibited cultures, exogenous lactate stimulated entry into S and proliferation to a significantly higher saturation density. CONCLUSIONS: These findings indicate that exogenous lactate interferes with mechanisms of cell-cycle control at two different points in the cell-cycle, depending on cell density and the resulting absence or presence of inhibition of cell proliferation. Interference with cell-cycle control may underly the modification by exogenous lactate of radiosensitivity and postirradiation repair capacity in mammalian cells.

Putative non-Mendelian transmission of retinoblastoma in males: a phenotypic segregation analysis of 150 pedigrees.

In a previous genotypic study of eight families, we described paternal segregation distortion favoring the transmission of mutant alleles at the retinoblastoma gene locus (RB1). In the current study, we reviewed all published retinoblastoma pedigrees with defined ascertainment (n = 150), to determine whether the phenotypic segregation frequency at the RB1 locus is in general influenced by the sex of the transmitting parent. Segregation analysis under complete ascertainment revealed that 49.1% of the offspring of male transmitters were affected, while 44.3% of the offspring of female transmitters were affected. While this difference is not statistically significant, it is consistent with the previous findings. No significant sex distortion could be detected among the progeny of carrier fathers and mothers. In order to quantify the transmission ratio more precisely further prospective molecular genetic analysis is warranted. We propose a biological mechanism to account for a putative segregation distortion, namely that genetic recombination creates clones of spermatogonia that are homozygous for the mutant RB1 allele leading to a non-Mendelian ratio of sperm. This model can be experimentally tested using amplification of DNA from single sperm cells.

Turcot's syndrome of glioma and polyposis occurs in the absence of germ line mutations of exons 5 to 9 of the p53 gene.

The term "Turcot's syndrome" has been used to describe approximatively 55 patients with an association of colonic polyposis and primary neuroepithelial tumors of the central nervous system. The p53 tumor suppressor gene is a possible candidate underlying the syndrome because (a) mutations in the p53 gene are ubiquitous in human cancer, including colon carcinoma and gliomas, and (b) somatic or germ line mutations of the p53 tumor suppressor gene cause the Li-Fraumeni syndrome, which is characterized by the association of breast and soft tissue tumors. We determined the DNA sequence of the conserved regions of the p53 gene (exons 5 to 9) in the tumor tissues and lymphocytes of two patients with glioma-polyposis and found that mutations did occur as independent tumor-specific alterations but did not involve the germ line of these patients, suggesting that p53 may play a role in progression but not initiation of the disease.

Detection of aneuploid subpopulations in colon cancer biopsies by cultivation in vitro prior to flow cytometric analysis.

Flow cytometry offers a relatively simple method to determine the DNA content of colorectal cancers. However, the technique can not discover minor changes in karyotype which may characterize near-diploid tumors, nor will it detect very small populations of aneuploid cells. In an attempt to improve the detection of such cells, we incubated biopsy material prior to analysis. This method revealed an aneuploid subpopulation in one of two biopsies studied. This simple protocol may ultimately lead to a more accurate assessment of the ploidy in colon cancer.

[Hereditary colorectal cancer: observations of a family study]. / Le cancer colo-rectal héréditaire: à propos d'une observation familiale.

Described in Switzerland in the early '60, the major features of hereditary non-polyposis colon cancer syndrome (HNPCCS) were established 20 years ago by H. T. Lynch. HNPCCS accounts for at least 60% of the colon cancer etiology. Cancer family syndrome is defined by the presence of extracolonic primary tumors in addition to colon cancer. Both syndromes are transmitted by an autosomic dominant pattern. None of the known biomarkers are specific and/or sensitive enough to rely on their predictive values of patient's risks. A typical Swiss family was investigated on the basis of the cancer-prone family history. 21% of the family members observed over 5 generations presented one or more (30% of the cases) colo-rectal neoplasms at the age of 50. 55% of the tumors were right sided. Histologically, half of the tumors were mucinous. 30% of metachronous cancer appeared within 10 years. Polyps (1-3) and flat adenomas were associated to the lesion in 57%. Extra-colonic tumors appeared in 18% of family members and in half of the colon cancer patients. The sites of these tumors were the urinary tract, ovary, small bowel, breast and stomach. Two fibroblast strains of affected individuals were established. No increased tetraploidy was noted. Preliminary results suggest that this two strains are rather sensitive to ionising radiation. Often neglected, family history of colon cancer remains the major diagnostic and decision-making tool of a such syndrome. It will necessitate special treatment of affected subjects and early screening of the relatives.(ABSTRACT TRUNCATED AT 250 WORDS)