tbuckley/cabot-search huggingface dataset:
Prognostic Classification Factors Associated With Development of Multiple Autoantibodies, Dysglycemia, and Type 1 Diabetes—A Recursive Partitioning Analysis
Authors: Ping Xu, Jeffrey P. Krischer
Journal: Diabetes Care (2016)

OBJECTIVE To define prognostic classification factors associated with the progression from single to multiple autoantibodies, multiple autoantibodies to dysglycemia, and dysglycemia to type 1 diabetes onset in relatives of individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS Three distinct cohorts of subjects from the Type 1 Diabetes TrialNet Pathway to Prevention Study were investigated separately. A recursive partitioning analysis (RPA) was used to determine the risk classes. Clinical characteristics, including genotype, antibody titers, and metabolic markers were analyzed. RESULTS Age and GAD65 autoantibody (GAD65Ab) titers defined three risk classes for progression from single to multiple autoantibodies. The 5-year risk was 11% for those subjects &amp;gt;16 years of age with low GAD65Ab titers, 29% for those ≤16 years of age with low GAD65Ab titers, and 45% for those subjects with high GAD65Ab titers regardless of age. Progression to dysglycemia was associated with islet antigen 2 Ab titers, and 2-h glucose and fasting C-peptide levels. The 5-year risk is 28%, 39%, and 51% for respective risk classes defined by the three predictors. Progression to type 1 diabetes was associated with the number of positive autoantibodies, peak C-peptide level, HbA1c level, and age. Four risk classes defined by RPA had a 5-year risk of 9%, 33%, 62%, and 80%, respectively. CONCLUSIONS The use of RPA offered a new classification approach that could predict the timing of transitions from one preclinical stage to the next in the development of type 1 diabetes. Using these RPA classes, new prevention techniques can be tailored based on the individual prognostic risk characteristics at different preclinical stages.
Case 1-1993
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Richard L. Kradin, Eugene J. Mark
Journal: New England Journal of Medicine (1993)

Presentation of CaseA seven-year-old girl was admitted to the hospital because of a fourth episode of sore throat, dyspnea, and fever.The child had been born after 35 weeks of gestation to a mother 36 years old (her third pregnancy). The pregnancy was complicated by gestational hypertension but not by the use of medications, cigarettes, or alcohol. Elective cesarean section was performed under general anesthesia one day after spontaneous rupture of the membranes. The patient had been an unexpected fraternal twin, and her respiratory status at birth had been very depressed, with Apgar scores of 2.1 at one minute . . .
Observations and Comments on Failure of Dexamethasone Suppression
Authors: Julius E. Linn, Braxton Bowdoin, T. Albert Farmer, Clifton K. Meador
Journal: New England Journal of Medicine (1967)

IN most patients with Cushing's disease∥ urinary 17-hydroxycorticosteroids (17OHCS) are readily suppressed by 8 mg. of dexamethasone per day. However, Liddle,1 in 1960, predicted that the excessive amounts of cortisol in some cases of this disease would not be suppressible with this amount of dexamethasone, and in 1962, Scott and his associates2 reported such a case. There have been reports of other patients with bilateral adrenocortical lesions with high levels of cortisol resistant to dexamethasone suppression.3 4 5 6 7 8 9 10 Failure to appreciate the variable significance of this phenomenon and the previous unavailability of plasma ACTH assays have resulted in the divergent interpretations of . . .
Insights into epidemiology of human parvovirus B19 and detection of an unusual genotype 2 variant, Bulgaria, 2004 to 2013
Authors: Stefka Krumova Ivanova, Zafira Georgieva Mihneva, Andon Krumov Toshev, Valentina Pavlova Kovaleva, Lubena Georgieva Andonova, Claude P Muller, Judith M Hübschen
Journal: Eurosurveillance (2016)

The present study aimed to determine the role of human parvovirus В19 (B19V) as an aetiological agent in measles and rubella negative fever/rash patients from Bulgaria between 2004 and 2013. A total of 1,266 sera from all over the country were tested for B19V IgM antibodies and all positives were further investigated by polymerase chain reaction (PCR). Overall, 280 sera (22%) were B19V IgM positive and 227 of these (81%) were also PCR positive. The highest number of IgM positives was found among five to nine year-old children (27%). Eight infected women gave birth to healthy children; one fetus was aborted with hydrops fetalis. Of the 55 genetic sequences obtained, 54 belonged to genotype 1a and one grouped as a genotype 2 outlier. Phylogenetic analysis of all available genotype 2 sequences covering the 994 nucleotide non-structural protein 1(NS1)/capsid viral protein 1 (VP1) unique region junction, showed that only one other sequence grouped with the outlier strain, forming a clearly distinct and well-supported cluster of genotype 2 (between-group genetic distance: 3.32%). In accordance with B19V nomenclature, this cluster may represent a new subgenotype 2b. The study showed that B19V infections may be falsely identified as rubella or measles in ca 22% of cases, emphasising the need for laboratory confirmation.
GENO-26IDENTIFICATION OF GENOMIC LESIONS ENRICHED IN LUNG CANCER BRAIN METASTASES
Authors: Sharon Michelhaugh, Aliccia Bollig-Fischer, Sandeep Mittal
Journal: Neuro-Oncology (2015)

BACKGROUND: The incidence of central nervous system metastasis from primary non-small cell lung cancer (NSCLC) has steadily increased despite the introduction of more effective targeted therapies. Current standard-of-care treatment modalities for CNS metastases include microsurgical resection, stereotactic radiosurgery, and whole-brain radiation therapy, either alone or in combination. There are currently FDA-approved drugs with indications for metastatic lung cancer, however, they have limited effectiveness against brain metastases. Clearly, there is a dire need to identify biomarkers permitting earlier and accurate diagnosis of CNS metastases. METHODS: DNA isolated from 27 fresh-frozen NSCLC metastatic brain tumors (MBTs), including both adenocarcinoma and squamous cell carcinoma subtypes, was quantified and analyzed by array comparative genomic hybridization (aCGH) using Agilent SurePrint arrays (G3 ISCA CGH + SNP 180K) and commercially-available, genetically-normal female or male DNA standard. Bioinformatics analysis was performed using Agilent Cytogenomics software. Data were filtered against the Cancer Gene Census (Wellcome Trust Sanger Institute) to identify genes with well-characterized roles in cancer. RESULTS: From our genomic copy number aberration (CNA) data analysis tailored to uncover recurring gene aberrations in NSCLC MBTs, we identified SOX2, PIKC3A, MYC, and CCDN1 amplifications in 22%, 19%, 15% and 15% of MBT specimens, respectively. Of these, targeted therapeutics have been developed for PIKC3A (dactolisib, SF1126, and PX-866) and CCDN1 (daunorubicin and gemtuzumab). CONCLUSIONS: These genes are known drivers of cancer cell phenotypes and are targets of new drug development and warrant further study to determine their suitability as biomarkers for advancing treatment strategies for brain metastases in NSCLC patients.
The Place of BCG Vaccine in the Management of Infants Born of Tuberculous Mothers
Authors: Edwin L. Kendig
Journal: New England Journal of Medicine (1969)

One hundred and five infants, born of tuberculous mothers, have been followed a mean of 11 years. Thirty received BCG vaccine; all are alive, and none contracted tuberculosis. Of 75 nonvaccinated infants, 38 became infected with tuberculosis; six died (two with tuberculous meningitis, one with acute gastroenteritis and inactive pulmonary tuberculosis and three with nontuberculous disease). This experience and the known inadequacies of an imperfectly followed regimen of simple isolation, surveillance or isoniazid prophylaxis combine to make BCG vaccination the method of choice for prevention of tuberculosis in newborn infants of tuberculous mothers.
A Prospective Evaluation and Follow-up of Patients with Syncope
Authors: Wishwa N. Kapoor, Michael Karpf, Sam Wieand, Jacqueline R. Peterson, Gerald S. Levey
Journal: New England Journal of Medicine (1983)

We prospectively evaluated and followed 204 patients with syncope to determine how often a cause of syncope could be established and to define the prognosis of such patients. A cardiovascular cause was established in 53 patients and a noncardiovascular cause in 54. The cause remained unknown in 97 patients. At 12 months, the overall mortality was 14 +/- 2.5 per cent. The mortality rate (30 +/- 6.7 per cent) in patients with a cardiovascular cause of syncope was significantly higher than the rate (12 +/- 4.4 per cent) in patients with a noncardiovascular cause (P = 0.02) and the rate (6.4 +/- 2.8 per cent) in patients with syncope of unknown origin (P less than 0.0001). The incidence of sudden death was 24 +/- 6.6 per cent in patients with a cardiovascular cause, as compared with 4 +/- 2.7 per cent in patients with a noncardiovascular cause (P = 0.005) and 3 +/- 1.8 per cent in patients with syncope of unknown origin (P = 0.0002). Patients with syncope can be separated into diagnostic categories that have prognostic importance. Patients with a cardiovascular cause have a strikingly higher incidence of sudden death than patients with a noncardiovascular or unknown cause.
Sipholenol A, a marine-derived sipholane triterpene, potently reverses P-glycoprotein-mediated multidrug mesistance in cancer cells
Authors: Zhi Shi, Sandeep Jain, In-Wha Kim, Xing-Xiang Peng, Ioana Abraham, Li-Wu Fu, Diaa Youssef, Khalid El Sayed, Suresh Ambudkar, Zhe-Sheng Chen
Journal: Cancer Research (2007)

2288   The marine ecosystem represents most of the species on the earth, and marine organisms provide numerous sources to develop novel compounds with multiple pharmacological potentials, including antiviral, antibacterial, anti-inflammatory, and anticancer and so on. The analgesic Conotoxin MVIIA (Prialt®) represents the first marine natural product drug to be introduced to the market. A number of marine compounds are currently in various phases of human clinical trials to treat different cancers, such as ecteinascidin, squalamine, aplidin, bryostatin-1, dolastatin-10 and ILX651. In this study, we screened thirty new marine sponge compounds to investigate their anticancer effects and inhibition of the activity of P-glycoprotein (P-gp, ABCB1) to reverse multidrug resistance (MDR) in human cancer cells. When these compounds were tested in two human drug-selected MDR cell lines KB-C2 and KB-V1, we found that one of the sipholane triterpenes, sipholenol A, in a concentration-dependent manner potentiated the cytotoxicity of several anticancer drugs including colchicine, vinblastine, and paclitaxel and significantly reversed the resistance of MDR cancer cells. Furthermore, sipholenol A had no effect on the response to cytotoxic agents in cells lacking P-gp expression or expressing other MDR-linked transporters including MRP1 (ABCC1) or breast cancer resistance protein (BCRP, ABCG2), and was not cytotoxic by itself at 50 μM, regardless of P-gp status. Accumulation and efflux studies with the P-gp substrate [ 3 H]-paclitaxel demonstrated that sipholenol A time-dependently increased the intracellular accumulation of [ 3 H]-paclitaxel by directly inhibiting P-gp-mediated drug efflux. In addition, sipholenol A did not have any effect on the expression of P-gp after treating MDR cancer cells for seventy-two hours, however, it did inhibit the photolabeling of P-gp with [ 125 I]- Iodoarylazidoprazosin. We conclude that sipholenol A interacts directly with P-gp and sipholane triterpenes are a new class of potential reversing agents for treatment of MDR in P-gp overexpressing tumors.
Meta-analysis on the relationship between everolimus exposure and safety and efficacy.
Authors: Dalila B. Sellami, Shweta Ramesh Urva, Kai Grosch, Wing Kui Cheung, Ozlem Anak
Journal: Journal of Clinical Oncology (2012)

3099 Background: Data on everolimus exposure–safety and response relationships are available from individual studies. We performed a meta-analysis to assess these relationships using everolimus predose minimum blood concentration (C min ). Methods: Individual patient data from 5 phase 2 or 3 oncology studies in which steady-state predose pharmacokinetic samples were taken from patients administered everolimus monotherapy 10 mg/day were pooled. In a Cox regression, the times to first grade ≥3 select adverse events (AEs) associated with everolimus and first progression-free survival (PFS) event were related to log-transformed instant or time-averaged C min as time-varying covariates stratified by study. Probability of tumor size reduction according to RECIST (yes vs no) was assessed using a generalized linear mixed model fitted with GEE method with log-transformed instant or time-averaged C min as covariates and treatment arm as fixed effect. Results: 945 patients were evaluable for efficacy, 938 for safety. Patient characteristics were relatively well balanced across studies. Regardless of whether instant or time-averaged C min was used, a 2-fold increase in everolimus exposure increased the risk of grade ≥3 pulmonary, metabolic, and stomatitis events (Table); no increased risk of other grade ≥3 AEs was observed. A 2-fold increase in everolimus exposure increased the likelihood of tumor size reduction; there was a trend of reduced risk of a PFS event (Table). Conclusions: A 2-fold increase in everolimus exposure is associated with a higher probability of tumor size reduction and increased risk of high-grade pulmonary, metabolic, and stomatitis AEs associated with everolimus. [Table: see text]
Clinical trials and rare diseases
Authors: C K Connolly
Journal: BMJ (1996)

Follicular CD8<sup>+</sup> T (fCD8) cells reside within B cell follicles and are thought to be immune-privileged sites of HIV/SIV infection. We have observed comparable levels of fCD8 cells between chronically SIV-infected rhesus macaques with low viral loads (LVL) and high viral loads (HVL), raising the question concerning their contribution to viremia control. In this study, we sought to clarify the role of SIV-specific fCD8 cells in lymph nodes during the course of SIV infection in rhesus macaques. We observed that fCD8 cells, T follicular helper (Tfh) cells, and T follicular regulatory cells (Tfreg) were all elevated in chronic SIV infection. fCD8 cells of LVL animals tended to express more Gag-specific granzyme B and exhibited significantly greater killing than did HVL animals, and their cell frequencies were negatively correlated with viremia, suggesting a role in viremia control. Env- and Gag-specific IL-21<sup>+</sup> Tfh of LVL but not HVL macaques negatively correlated with viral load, suggesting better provision of T cell help to fCD8 cells. Tfreg positively correlated with fCD8 cells in LVL animals and negatively correlated with viremia, suggesting a potential benefit of Tfreg via suppression of chronic inflammation. In contrast, in HVL macaques, Tfreg and fCD8 cell frequencies tended to be negatively correlated, and a positive correlation was seen between Tfreg number and viremia, suggesting possible dysfunction and suppression of an effective fCD8 cell immune response. Our data suggest that control of virus-infected cells in B cell follicles not only depends on fCD8 cell cytotoxicity but also on complex fCD8 cell associations with Tfh cells and Tfreg.
US health officials press Congress for $1.9bn to combat Zika
Authors: Michael McCarthy
Journal: BMJ (2016)

US health officials said yesterday that their agencies do not have enough money to respond to the threat to public health posed by the Zika virus and called on Congress to appropriate the $1.9bn (£1.3bn; €1.7bn) in emergency funding that President Barack Obama requested.

The president sought the funding in February,1 but Republicans in Congress, who control the House of Representatives and the Senate, declined to appropriate the funds, saying that the administration should instead draw on unspent funds that had been appropriated to combat the outbreak of Ebola virus disease in west Africa. The administration argued …
Global Trends in Resistance to Antituberculosis Drugs
Authors: Marcos A. Espinal, Adalbert Laszlo, Lone Simonsen, Fadila Boulahbal, Sang Jae Kim, Ana Reniero, Sven Hoffner, Hans L. Rieder, Nancy Binkin, Christopher Dye, Rosamund Williams, Mario C. Raviglione
Journal: New England Journal of Medicine (2001)

We expanded the survey conducted by the World Health Organization and the International Union against Tuberculosis and Lung Disease to assess trends in resistance to antituberculosis drugs in countries on six continents. We obtained data using standard protocols from ongoing surveillance or from surveys of representative samples of all patients with tuberculosis. The standard sampling techniques distinguished between new and previously treated patients, and laboratory performance was checked by means of an international program of quality assurance.
Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy
Authors: Maria Stella Sasso, Giovanna Lollo, Marion Pitorre, Samantha Solito, Laura Pinton, Sara Valpione, Guillaume Bastiat, Susanna Mandruzzato, Vincenzo Bronte, Ilaria Marigo, Jean-Pierre Benoit
Journal: Biomaterials (2016)
Surgery for Seizures
Authors: Jerome Engel
Journal: New England Journal of Medicine (1996)

Of the approximately 2 million Americans with a diagnosis of epilepsy who are treated with antiepileptic drugs, 20 percent continue to have seizures1; this group of patients accounts for over 75 percent of the cost of epilepsy in the United States.2 For many of those with medically refractory epilepsy, their disability can be completely eliminated by surgical intervention. Only a small percentage of potential surgical candidates, however, are currently referred to epilepsy-surgery centers.3 OverviewThe classic 1886 paper of Victor Horsley4 heralded the modern era of epilepsy surgery, and the introduction of electroencephalography (EEG) in the first half of . . .
Clinical Value of Serum Leucine Aminopeptidase Determinations
Authors: Benjamin M. Banks, Esteban P. Pineda, Julius A. Goldbarg, Alexander M. Rutenburg
Journal: New England Journal of Medicine (1960)

LEUCINE aminopeptidase is a proteolytic enzyme widely distributed in human tissues and body fluids. This report deals with an evaluation of the clinical usefulness of serum assays of this enzyme as determined by the hydrolysis of L-leucyl-beta-naphthylamide. The results obtained with this substrate and their interpretation differ from those obtained with the use of the substrate L-leucylglycine.1 2 3 Our method of assay4 , 5 is a modification of colorimetric methods described by others.6 7 8 9 The validity of this modified method has been established.4 With it, the upper limits of normal, taken as 2 standard deviations above the normal mean, are 200 units for males . . .
Putting the Family Back in Medical Education
Authors: Kenneth E. Appel
Journal: New England Journal of Medicine (1953)

SIGERIST has described the function of medicine as follows:The task of medicine is to promote health, to prevent disease, to treat the sick when prevention has broken down and to rehabilitate people after they have been cured. These are highly social functions and we must look at medicine as basically a social science — one link in a chain of social welfare institutions that every civilized country must develop. If we have a maladjustment today, it is to a large extent due to the fact that we have neglected the sociology of medicine. The technology of medicine has outrun . . .
ATCT-07PHASE 2 STUDY OF MEDI-575, AN ANTI-PLATELET-DERIVED GROWTH FACTOR-α ANTIBODY, IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Surasak Phuphanich, Jeffrey Raizer, Marc Chamberlain, Paola Canelos, Rajesh Narwal, Shengyan Hong, Robert Miday, Minal Nade, Kevin Laubscher
Journal: Neuro-Oncology (2015)

MEDI-575, an immunoglobulin G2κ monoclonal antibody, selectively binds to platelet-derived growth factor-α receptor (PDGFR-α) with high specificity. This multicenter, single-arm, open-label, phase II study evaluated the efficacy and safety of MEDI-575 in patients with recurrent glioblastoma. Adults with first recurrence of glioblastoma following surgery, temozolomide, and radiation received MEDI-575 25 mg/kg intravenously over 60 min every 21 days until disease progression or unacceptable toxicity. Six-month progression-free survival rate (PFS-6) was the primary end point; secondary measures included response rate, overall survival (OS), and safety/tolerability. PDGFR-α expression was evaluated by immunohistochemistry. Fifty-six patients were enrolled; median age was 56.5 years (range 23–79), 66 % were male, and 66 % were aged ≥65 years. PFS-6 was 15.4 % [90 % confidence interval (CI) 8.1–24.9]. No complete or partial responses were observed; 23 (41.1 %) patients had stable disease as best response. Median PFS was 1.4 months (90 % CI 1.4, 1.8); median OS was 9.7 months (90 % CI 6.5, 11.8). The most common treatment-related adverse events (AEs) were diarrhea (16 %), nausea (13 %), and fatigue (13 %). Twelve (21 %) patients reported grade ≥3 AEs, with hydrocephalus (n = 3), dysphagia (n = 2), and convulsion (n = 2) reported in more than 1 patient. Two patients had treatment-related Grade ≥3 AEs of decreased lymphocyte count and asthenia (n = 1 each). Seven patients (13 %) discontinued MEDI-575 owing to AEs. Labeling of PDGFRα in glioblastoma cells and tumor-associated stromal cells was highly variable, with no correlation with PFS. MEDI-575, although well tolerated, had limited clinical activity in recurrent glioblastoma.
Zika Virus Disease
Authors: Jill Jin
Journal: JAMA (2016)

Zika virus disease is generally a mild illness, but it can cause serious birth defects when it affects pregnant women.

Zika virus disease is caused by the Zika virus, which is spread to people by mosquito bites. An estimated 80% of people who get Zika have no symptoms. When symptoms appear, they are usually mild, last a few days to a week, and go away on their own. The most common symptoms are fever, rash, joint pain, and red eyes. Although most Zika infection is spread by mosquito bites, it can also be spread from mother to child in pregnant women and can be sexually transmitted. There is currently no treatment for Zika.
Who Killed my Baby?
Authors: Harvey Marcovitch
Journal: BMJ (2005)

Channel 4, 23 June at 9 pm Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img>![Graphic][4]</img> Items reviewed are rated on a 4 star scale (4=excellent) T owards the end of this powerful documentary, Stephanie Drake, whose son in law was convicted of the manslaughter of her grandson, said: "They're not going to take someone to court for no reason. They don't convict innocent people… really." Her daughter, Katrina, from whom she is now estranged, sees it differently: "It's unfair… we had four weeks of medical evidence. The jury don't know anything medical. They had to ask what 'paediatrician' meant," she said. Katrina's partner, Jo, was alone with their 4 month old son, Joshua, when the baby stopped breathing. In recounting events, Who Killed my Baby? played the recording of Jo's desperate call to the emergency services and informed viewers that Joshua was found to have subdural haemorrhage, cerebral oedema, and retinal haemorrhages, characteristic of what has become known to the public as "shaken baby syndrome." The treating specialist, whose job title was so unfamiliar to the trial jury, explained his duty to report a baby with brain injury … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif [4]: /embed/inline-graphic-4.gif