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Biomedical subjects

D Weinberg

Publications and source records attributed to D Weinberg.

At least 19 recordsLinked to original sources

Breast cancer treatment in clinical practice compared to best evidence and practice guidelines.

There is sparse evidence on community practice patterns in treating women with breast cancer. This study compared care of women with breast cancer with evidence from meta-analyses and US National Comprehensive Cancer Network (NCCN) clinical guidelines. Records of 4395 women with breast cancer were abstracted from practices of 19 surgeon oncologists in six specialty practices in the Philadelphia region during 1995-1999. Patients were followed through December 2001. Low-frequency data were obtained on all patients. All other data were from a random sample of 464 women, minimum of 50 patients per practice. Actual care provided was compared to NCCN guidelines and results of meta-analyses. Fewer than half the women received treatments reflecting meta-analysis results or NCCN guidelines, by disease stage/TNM status. Adherence to either standard varied from 0% for LCIS to 87% for stages IIA or IIB node positive. There are multiple interactive reasons for low adherence to guidelines or meta-analyses results, including insufficient health system supports to clinicians, inadequate organisation and delivery systems and ineffective continuing medical education. The paucity of written information from patient records on physician/patient interactions limits the understanding of treatment decisions.

Adult↗

Extensive structure-activity studies of lactam derivatives of MT-II and SHU-9119: their activity and selectivity at human melanocortin receptors 3, 4, and 5.

The melanocortin system is involved in the regulation of several diverse physiologic pathways. Recently we have demonstrated that replacing His6 by Pro6 in the well-known antagonist SHU-9119 resulted in a potent agonist at the hMC5R (EC50 = 0.072 nm) with full antagonist activity at the hMC3R and the hMC4R. We have designed, synthesized, and pharmacologically characterized a series of peptide analogs of MT-II and SHU-9119 at the human melanocortin receptors MC3R, MC4R and MC5R. All these peptides were modified at position 6 with a Pro instead of a His residue. In this study, we have identified new scaffolds which are antagonists at the hMC4R and hMC3R. Additionally, we have discovered a new selective agonist at the hMC4R, Ac-Nle-c[Asp-Pro-D-Phe-Arg-Trp-Lys]-Pro-Val-NH2 (6, PG-931) which will be useful in further biologic investigations of the hMC4R. PG-931 was about 100-fold more selective for the hMC4R vs. the hMC3R (IC50 = 0.58 and 55 nm, respectively). Some of these new analogs have exceptional biologic potencies at the hMC5R and will be useful in further efforts to differentiate the substructural features responsible for selectivity at the hMC3R, hMC4R, and hMC5R.

Animals↗

Synthesis and biological evaluation on hMC3, hMC4 and hMC5 receptors of gamma-MSH analogs substituted with L-alanine.

To elucidate the molecular basis of the interaction of the native dodecapeptide gamma-MSH with the melanocortin receptors, we performed a structure-activity study in which we systematically replaced l-Ala in each position of this peptide. Here we report the binding affinity and agonist potency on human MC3R, MC4R and MC5R. Intracellular cAMP concentration was measured on CHO cells, and binding assays were carried out using membranes prepared from these cell lines which stably express hMC3R, hMC4R and hMC5R. Our results indicate that the last four amino acids in the C-terminal region of gamma-MSH are not important determinants of biological activity and selectivity at human melanocortin receptors. Interesting results were obtained when l-Ala was substituted for His6, Phe7, Arg8 and Trp9. For these peptides, the affinity and activity at all three human receptors (MC3R, MC4R and MC5R) decreased significantly, demonstrating that the His-Phe-Arg-Trp sequence in gamma-MSH is important for activity at these three melanocortin receptors. Similar results were obtained when Met3 was replaced with l-Ala, suggesting the importance of this position in the interaction with all three receptors. This study highlights the role played by the His-Phe-Arg-Trp sequence in receptor binding and in agonist activity of gamma-MSH.

Alanine↗

Ectopic expression of guanylyl cyclase C in CD34+ progenitor cells in peripheral blood.

PURPOSE: To examine the utility of guanylyl cyclase C (GC-C)-specific nested reverse transcriptase polymerase chain reaction (RT-PCR) to detect circulating tumor cells in patients with colorectal cancer. PATIENTS AND METHODS: Peripheral-blood mononuclear cells from 24 patients with Dukes' stage D colorectal cancer were analyzed by GC-C-specific nested RT-PCR using 1 microg of total RNA. Peripheral-blood mononuclear cells from 20 healthy volunteers served as controls. Additionally, peripheral-blood CD34+ progenitor cells were assayed for the expression of both GC-C and other epithelial cell-specific markers. RESULTS: GC-C mRNA was detected in blood mononuclear cells from all 24 patients with colorectal cancer and all healthy volunteers. These unexpected positive results reflected low-level ectopic transcription of GC-C in CD34+ progenitor cells. Moreover, CD34+ progenitor cells expressed other epithelial cell-specific markers, including prostate-specific antigen, prostate-specific membrane antigen, carcinoembryonic antigen, CK-19, CK-20, mucin 1, and GA733.2. Limiting the quantity of mononuclear cell total RNA analyzed to < or = 0.8 microg eliminated detection of GC-C and other tissue-specific transcripts in blood of healthy volunteers. However, under the same conditions, GC-C mRNA was detected in mononuclear cells from all 24 patients with metastatic colorectal cancer. Using 0.5 microg of total RNA and GC-C-specific primers, nested RT-PCR detected a single human colon carcinoma cell (approximately 20 to 200 GC-C transcripts/cell) in 10(6) to 10(7) mononuclear blood cells. CONCLUSION: These data suggest that GC-C may be useful for detecting circulating colorectal cancer cells. They also demonstrate that CD34+ cells are a source of ectopically expressed epithelial cell-specific markers and that CD34+ cells may contribute to the high false-positive rate generally observed when those markers are used to detect rare circulating metastatic cancer cells by RT-PCR.

Adult↗

Left ventricular geometry and operative mortality in patients undergoing mitral valve replacement.

BACKGROUND: Distortion of left ventricular (LV) shape is often associated with LV dysfunction and is thought to be an independent predictor of survival in patients with coronary disease. HYPOTHESIS: The purpose of this study was to examine the relationship between LV geometry and hospital mortality in patients with mitral regurgitation (MR) undergoing mitral valve surgery. METHODS: A consecutive series of patients (aged 68+/-12 years, 47% men) (n = 149) with MR who underwent cardiac catheterization, left ventriculography, and mitral valve surgery from 1995 to 1996 at Mount Sinai Medical Center was studied. Left ventriculograms, clinical records, and hemodynamics were reviewed. Left ventricular volumes and ejection fraction were calculated using standard techniques. Left ventricular shape in diastole and systole was evaluated using the sphericity index, which is defined as the end-systolic LV volume (x 100) divided by the volume of a sphere whose diameter is equal to the LV long axis. RESULTS: In the patients studied, the etiology of mitral insufficiency was mitral valve prolapse in 40.9%, ischemic heart disease in 40.3%, rheumatic heart disease in 11.4%, and prosthetic valvular dysfunction in 7.4%. The average ejection fraction was 65%+/-17. Systolic sphericity index (SSI) was 36%+/-15 in patients who died, compared with 25%+/-11 in patients who lived (p < 0.001). A multivariate model was constructed using hemodynamic and angiographic indices derived during preoperative cardiac catheterization. Systolic sphericity index (odds ratio = 1.6 for each point increase, p < 0.01) was found to be an independent predictor of postoperative survival in the global population, as well as in patients with coronary disease (p<0.01). CONCLUSION: Left ventricular geometry is an independent angiographic risk factor for survival following mitral valve replacement. Sphericity index is a simple method for assessing LV geometry which should be calculated in patients as part of risk stratification.

Adult↗

Complete diagnostic evaluation in colorectal cancer screening: research design and baseline findings.

BACKGROUND: While indicated by guidelines, complete diagnostic evaluation, or CDE (i.e., colonoscopy or combined flexible sigmoidoscopy plus barium enema X ray), is often not recommended and performed for persons with an abnormal screening fecal occult blood test (FOBT) result. We initiated a randomized trial to assess the impact of a physician-oriented intervention on CDE rates in primary care practices. METHODS: In 1998, we identified 1,184 primary care physicians (PCPs) in 584 practices whose patients received FOBTs that are mailed annually by a managed care organization screening program. A total of 470 PCPs in 318 practices completed a baseline survey. Practices were randomly assigned either to a Control Group (N = 198) or to an Intervention Group (N = 120). Control Group practices received the screening program. Intervention Group practices received the screening program and the intervention (i.e., CDE reminder-feedback plus educational outreach). Practice CDE recommendation and performance rates are the primary outcomes to be measured in the study. RESULTS: Baseline CDE recommendation and performance rates were low and were comparable in Control and Intervention Group practices (54 to 57% and 39 to 40%, respectively). PCPs in the practices tended to view FOBT screening and CDE favorably, but had concerns about screening efficacy, time involved in CDE, and patient discomfort and adherence. Control Group physicians were more likely than Intervention Group physicians to believe that a mail-out FOBT screening program helps in the practice of medicine. CONCLUSIONS: We were able to enroll a high proportion of targeted primary care practices, measure practice characteristics and CDE rates at baseline, and develop and implement the intervention. Study outcome analyses will take into account baseline differences in practice characteristics.

Analysis of Variance↗

D-Amino acid scan of gamma-melanocyte-stimulating hormone: importance of Trp(8) on human MC3 receptor selectivity.

In our search for potent and receptor-selective agonists and antagonists, we report here the results of D-amino acid substitution at each position of the short peptide gamma-melanocyte-stimulating hormone (gamma-MSH). The native gamma-MSH shows weak binding at all three receptors (i.e., the human MC3, MC4, and MC5) and a selectivity of 1-2 orders of magnitude at the MC3R over the MC4R and MC5R. Sequential replacement of each residue in the gamma-MSH sequence with the corresponding D-isomer results in analogues which mostly have weaker binding affinity than the native peptide, except for two analogues. For the DTrp(8) analogue, there is an increase in binding affinity by about 1 order of magnitude (IC(50) = 6 nM) at the MC3R compared with that of the natural molecule and an increase in selectivity for the MC3R by 2 orders of magnitude compared with the activity at the MC4R and MC5R. The DPhe(6) analogue is about 10-fold more potent (IC(50) = 8.8 nM) at the MC3R compared with the native peptide but lacks subtype selectivity. Measurement of the intracellular cAMP accumulation in human MC3R, MC4R, and MC5R revealed that the native peptide shows potent activity at the MC3R (EC(50) = 5.9 nM) and is about 50-100-fold selective at this receptor compared with the MC4R and MC5R. The DArg(10) (EC(50) = 35 nM) and DPhe(11) (EC(50) = 11 nM) analogues are selective for the MC3R by 1 and 2 orders of magnitude compared with the MC4R and MC5R, respectively. The DTrp(8) compound (EC(50) = 0.33 nM) shows about 300- and 250-fold increase in selectivity at the MC3R compared with the MC4R and MC5R, respectively. Finally, the DTyr(1) peptide is selective for the MC3R (EC(50) = 12 nM) by 40-200-fold compared with the MC4R and MC5R. In general, the trend is that D-amino acid substitutions of the aromatic residues 1, 6, 8, and 11 and the basic residue Arg(10), but not Arg(7), result in an increase in MC3R selectivity over the MC4R and MC5R and only agonist activity is observed. Thus, the key residues of gamma-MSH identified in this study include the aromatic residues 1, 6, 8, and 11 and the basic residue Arg(10) (but not Arg(7)), as important for MC3 selectivity over the MC4 and MC5 subtypes. Further, the study reveals the extreme importance of DTrp at position 8 in imparting potency and selectivity since this is the most selective analogue for the human MC3R reported thus far.

Amino Acid Substitution↗

Colorectal cancer staging and adjuvant chemotherapy.

Colorectal cancer is a significant cause of morbidity and mortality in Western populations. The standard of care for staging patients with colorectal cancer to determine prognosis and identify patients who will receive adjuvant therapy continues to be histopathology of regional lymph nodes. However, the significant variability in survival within each staging category likely reflects the heterogeneity of detecting micrometastatic disease employing this technique. Novel molecular markers of micrometastases currently in development will permit more accurate staging of patients with colorectal cancer. These advances in staging will distinguish patients who will maximally benefit from adjuvant therapy from those who have an especially good prognosis in whom chemotherapy can be avoided. In addition, new adjuvant chemotherapeutic agents, novel combinations of those agents and creative dosing schedules currently being investigated will offer considerable advantages with respect to ease of administration, safety and tolerability, quality of life and efficacy. Ultimately, it is anticipated that advances in molecular diagnostics will define unique biochemical characteristics of patients' tumours, permitting individualization of chemotherapeutic regimens employing novel agents that specifically exploit those characteristics.

Animals↗

Guanylyl cyclase C messenger RNA is a biomarker for recurrent stage II colorectal cancer.

BACKGROUND: Patients with stage II colorectal cancer and no histologic evidence of lymph node invasion develop recurrent disease, presumably because of undetected micrometastases. Guanylyl cyclase C is expressed by intestinal and colorectal cancer cells but not by extraintestinal tissues or tumors. OBJECTIVE: To examine the expression of guanylyl cyclase C messenger RNA (mRNA) in lymph nodes of patients with node-negative colorectal cancer who did and did not have recurrent disease. DESIGN: Case-control study. SETTING: Tertiary care academic medical center. PATIENTS: Paraffin-embedded lymph nodes were obtained from 21 patients with histologically confirmed node-negative colorectal cancer who had undergone resection. Controls included 11 patients without disease recurrence 6 or more years after resection, and case-patients included 10 patients whose disease recurred up to 3 years after resection. MEASUREMENTS: Sections of paraffin-embedded lymph nodes were obtained from each patient and were pooled, and their RNA was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Guanylyl cyclase C mRNA was expressed in lymph nodes from all patients with recurrent disease but not in those from patients without recurrent disease (P = 0.004). Nested RT-PCR that used primers for carcinoembryonic antigen, a marker for colorectal cancer, identified carcinoembryonic antigen mRNA in lymph nodes from only 1 of 10 patients with recurrent disease and those from 0 of 11 patients without recurrent disease. The odds ratio for death associated with expression of guanylyl cyclase C mRNA in regional lymph nodes was 15.0 (95% CI, 1.1 to 756.7). CONCLUSIONS: Expression of guanylyl cyclase C mRNA in lymph nodes is associated with recurrence of colorectal cancer in patients with stage II disease. Analysis of guanylyl cyclase mRNA expression by RT-PCR may be useful for colorectal cancer staging.

Adult↗

Physician intention to recommend complete diagnostic evaluation in colorectal cancer screening.

Primary care physicians (PCPs) often do not recommend complete diagnostic evaluation (CDE; i.e., diagnostic colonoscopy or the combination of flexible sigmoidoscopy and barium enema X-ray procedures) for patients with an abnormal screening fecal occult blood test (FOBT+) result. Information is needed to understand why PCPs do not recommend CDE. In the spring of 1994, a telephone survey was carried out using a random sample of 520 PCPs in Pennsylvania or New Jersey who had patients that were targeted for an FOBT screening program. Survey data were obtained from 363 (70%) PCPs on physician practice characteristics; personal background; perceptions concerning FOBT screening, CDE performance, and patient behavior; social influence related to CDE; and intention to recommend CDE for FOBT+ patients. Physician CDE intention scores were distributed as follows: low (22%), moderate (51%), and high (27%). Multivariate analyses demonstrate that physician board certification status, time in practice, belief in CDE efficacy, and belief that CDE is standard practice were positively associated with CDE intention, whereas concern about CDE-related costs was negatively associated with CDE intention. Among physicians in larger practices, perceived FOBT screening efficacy was negatively associated with CDE intention, and belief in the benefit of CDE was positively associated with outcome. There is substantial variability in CDE intention among PCPs. Physician perceptions about FOBT screening and follow-up are associated with CDE intention, are likely to influence CDE performance, and may be amenable to educational intervention. Additional research is needed to evaluate the impact of educational interventions on CDE intention and performance.

Adult↗

Use of guanylyl cyclase C for detecting micrometastases in lymph nodes of patients with colon cancer.

INTRODUCTION: Guanylyl cyclase C appears to be expressed only in colorectal cancer cells in extraintestinal tissues. Thus, guanylyl cyclase C may be useful as a marker to detect colorectal cancer micrometastases not detectable by histopathology in lymph nodes of patients. METHODS: Twelve patients with colon adenocarcinoma, Dukes Stages A through C2, and one patient with a tubulovillous adenoma were included in this study. Forty-two lymph nodes were collected from fresh surgical specimens, and each was examined by histopathology and reverse transcription followed by polymerase chain reaction using guanylyl cyclase C-specific primers. Histopathology identified colon cancer cells in 6 of 16 lymph nodes from five Dukes Stage C patients but not in lymph nodes from the patient with a tubulovillous adenoma, the Dukes Stage A patient, or six Dukes Stage B patients. Reverse transcription followed by polymerase chain reaction using guanylyl cyclase C-specific primers was performed on all 42 lymph nodes. RESULTS: Guanylyl cyclase C messenger RNA was not detected by reverse transcription followed by polymerase chain reaction in lymph nodes from the patient with the tubulovillous adenoma or the patient with Dukes Stage A colon carcinoma. Seven lymph nodes from Dukes Stage C patients revealed guanylyl cyclase C messenger RNA including six lymph nodes containing histopathologically confirmed metastases. Of significance, guanylyl cyclase C messenger RNA was detected in 6 of 21 lymph nodes from Dukes Stage B patients. Indeed, clinical staging of two patients could be upgraded from B to C using reverse transcription followed by polymerase chain reaction and guanylyl cyclase C-specific primers. CONCLUSION: Reverse transcription followed by polymerase chain reaction using guanylyl cyclase C-specific primers might be useful to more accurately assess micrometastases in lymph nodes of colorectal cancer patients undergoing disease staging.

Adenocarcinoma↗

Analysis of colorectal cancer stage among HMO members targeted for screening.

BACKGROUND: This study is a retrospective analysis of data collected from patient medical records, a fecal occult blood test (FOBT) screening program, and computerized health maintenance organization (HMO) claims and encounters records. OBJECTIVE: To identify factors associated with a diagnosis of early (Dukes A and B) colorectal cancer among older adults targeted for annual FOBT screening. METHODS: Study subjects were insured by the former US Healthcare Inc (Blue Bell, Pa), an independent practice association-type HMO. The HMO was recently integrated into Aetna-US Healthcare. Before diagnosis, subjects were eligible for free annual FOBT screening through the HMO's colorectal cancer screening program. The study subjects included men and women (N = 222) who were aged 50 years or older and had a diagnosis of colorectal cancer between 1987 and 1990. Variables considered were patient age, gender, socioeconomic status, medical history, screening history, length of enrollment in the HMO, and stage of disease at diagnosis. RESULTS: Univariate analyses indicate that colorectal cancer diagnosis due to FOBT screening (P = .03), frequency of FOBT screening (P = .09), and length of HMO membership (P = .10) were positively related to being diagnosed as having early stage colorectal cancer. Multivariable analysis shows that having a screen-detected colorectal cancer was significantly and positively related (P = .03) to being diagnosed as having early stage disease. CONCLUSIONS: Findings support annual FOBT screening among older adults. Results illustrate the value of applying standard methods to the collection and analysis of patient data in a managed care context. The study also highlights a need for research on patient adherence to screening and physician follow-up of abnormal screening test results.

Aged↗

ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors.

The mRNA encoding an agouti related protein (ART) of unknown biochemical function was previously reported to be up-regulated in the hypothalamus of two genetically obese mouse strains. We have expressed human ART as a secreted protein in COS-7 cells, and show that recombinant ART is functionally active in inhibiting the binding of a radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) analog to the human melanocortin-3 (MC-3) and melanocortin-4 (MC-4) receptors, while it is not a potent inhibitor of the human melanocortin-5 (MC-5) receptor. ART is an antagonist of the human MC-3 and MC-4 receptors as determined in functional assay. ART appears to be approximately 100-fold more potent than agouti with reference to the MC-3R and MC-4R binding affinity. These data suggest that ART may be a physiological regulator of feeding behavior.

Agouti-Related Protein↗

ACGT and vicilin core sequences in a promoter domain required for seed-specific expression of a 2S storage protein gene are recognized by the opaque-2 regulatory protein.

The expression of Brazil nut storage albumin genes is highly regulated during seed development. Several sequences in the promoter of one of these genes show homologies with the target sites of the maize O2 bZIP regulatory protein. We therefore asked whether the O2 protein would recognize these promoter sequences. We show that the O2 protein binds to three different sequences (F1, F2 and F3). F1 and F3 are hybrid C/G and A/G boxes, respectively, that are homologous to the O2-binding site of a maize alpha-zein gene. F2 is a new O2-binding sequence related to the O2 target sites of the Coix alpha-coxin, the maize b-32 genes and the AP-1 pseudopalindrome. Molecular modelling showed that an Asn and a Ser in the 02 DNA binding domain make different base-specific contacts with each operator. 5' Promoter deletions of the be2S1 gene showed that the domain containing the O2 target sites F1 and F2 is required for detectable reporter gene expression in transgenic tobacco seeds. Moreover, the homologous coix O2 protein was shown to in situ transactivate the promoter region encompassing the three O2-binding sites F1, F2 and F3. Thus, these sites may be in vivo regulatory sequences mediating activation by bZIP regulatory proteins.

2S Albumins, Plant↗

Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomised, placebo controlled trial.

BACKGROUND: Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. AIMS: To assess the efficacy of topical SCFA treatment in ulcerative colitis. PATIENTS AND METHODS: 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial. RESULTS: Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p = 0.14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (< 6 months, n = 42), more responded to SCFA than to placebo (48% v 18%, p = 0.03). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p = 0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p < 0.02) in their clinical and histological activity scores. CONCLUSIONS: Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit.

Acute Disease↗

Social model treatment and individuals with dual diagnoses: an ethnographic analysis of therapeutic practice.

Concurrent substance and psychiatric problems have been shown to significantly reduce the probability of successful treatment outcomes while increasing vulnerability to a range of troubles including homelessness, incarceration, physical health problems, and criminal victimization. This article presents an ethnographic analysis of treatment processes in a residential social model treatment program specifically designed for individuals with dual diagnoses in an effort to inform current debates with empirically grounded knowledge regarding therapeutic practice itself. The article focuses on four fundamental themes bearing on therapeutic practice in this residential program: social model treatment; the formulation of clinical identities; recovery, personal responsibility, and authority; and the measurement of therapeutic success. In conclusion, the article suggests that the central role played by program residents in the therapeutic process deserves particular attention and makes recommendations regarding mental health services delivery that, if followed, might invigorate treatment efficacy.

Adult↗

Evaluation of an international telepathology system between Boston (USA) and Dijon: glass slides versus telediagnostic television monitor.

A telepathology network developed by Resintel (Dijon) has proved valuable in interactive situations, where two physicians converse by telephone, showing each other the part of the lesion they wish to discuss. In future this interactive process could be replaced by an electronic mailing service in which a limited number of images are taken from the slide, but this technique needs to be assessed in comparison with traditional microscopic diagnosis, when the pathologist can screen the entire slide. The present study compared diagnoses achieved through the traditional methods of current pathology practice with diagnoses achieved through a selection of images on a telediagnostic TV monitor. The kappa coefficient between the two protocols was 0.26 (SE = 0.06), which allows us to conclude that there is a fair reliability between video and glass slide diagnoses.

Boston↗