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1.
Integr Comp Biol ; 60(3): 594-607, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32652006

ABSTRACT

Teeth lie at the interface between an animal and its environment and, with some exceptions, act as a major component of resource procurement through food acquisition and processing. Therefore, the shape of a tooth is closely tied to the type of food being eaten. This tight relationship is of use to biologists describing the natural history of species and given the high instance of tooth preservation in the fossil record, is especially useful for paleontologists. However, correlating gross tooth morphology to diet is only part of the story, and much more can be learned through the study of dental biomechanics. We can explore the mechanics of how teeth work, how different shapes evolved, and the underlying forces that constrain tooth shape. This review aims to provide an overview of the research on dental biomechanics, in both mammalian and non-mammalian teeth, and to synthesize two main approaches to dental biomechanics to develop an integrative framework for classifying and evaluating dental functional morphology. This framework relates food material properties to the dynamics of food processing, in particular how teeth transfer energy to food items, and how these mechanical considerations may have shaped the evolution of tooth morphology. We also review advances in technology and new techniques that have allowed more in-depth studies of tooth form and function.


Subject(s)
Biological Evolution , Tooth/physiology , Vertebrates/physiology , Animals , Biomechanical Phenomena
2.
Biol Lett ; 15(4): 20180905, 2019 04 26.
Article in English | MEDLINE | ID: mdl-30991915

ABSTRACT

It makes intuitive sense that you need a sharp tool to puncture through a tough material. The typical approach to evaluating sharpness in biological puncturing tools is to treat morphological measurements as a proxy for puncture ability. However, there are multiple approaches to measuring sharpness, and the relative influence of morphology on function remains unclear. Our goal is to determine what aspects of tip morphology have the greatest impact on puncture ability, using ( a) viper fangs and ( b) engineered punches to isolate the effects of different sharpness measures. Our results indicate that tip included angle is the strongest predictor of puncture performance in both viper fangs and engineered punches. For puncture tools with small included angles, sharpness index (based on the radius of curvature) also affects puncture ability. Finally, we found that punches serve as good predictors of fang performance at small angles and sharpness index values.


Subject(s)
Tooth , Viperidae , Animals , Punctures , Weights and Measures
3.
Proc Biol Sci ; 285(1891)2018 11 21.
Article in English | MEDLINE | ID: mdl-30464068

ABSTRACT

Spines are common morphological features found in almost all major biological groups offering an opportunity to explore large-scale evolutionary convergence across disparate clades. As an example, opuntioid cacti have spines with barbed ornamentation that is remarkably similar in form and scale to that found on porcupine quills, suggesting specific biomechanical convergence across the animal and plant kingdoms. While the mechanics of porcupine quills as defensive mechanisms has been previously tested, the mechanics of cactus spines (which have evolved to fill a number of functions including defence, climbing and dispersal) has not been characterized. Here we study the puncturing and anchoring ability of six species of cactus, including both barbed and non-barbed spines. We found that barbed spines require less work to puncture a variety of targets than non-barbed spines. Barbed spines also require more work than non-barbed spines to withdraw from biological materials, owing to their barbs engaging with tissue fibres. These results closely match those found previously for barbed versus non-barbed porcupine quills, implying biomechanical convergence. The variation in performance of barbed versus non-barbed spines, as well as between barbed spines from different species, is probably tied to the diversity of ecological functions of cactus spines.


Subject(s)
Cactaceae/anatomy & histology , Cactaceae/physiology , Mechanical Phenomena , Plant Leaves/anatomy & histology , Plant Leaves/physiology , Punctures
4.
J Exp Biol ; 219(Pt 21): 3399-3411, 2016 Nov 01.
Article in English | MEDLINE | ID: mdl-27807217

ABSTRACT

Countless aquatic animals rotate appendages through the water, yet fluid forces are typically modeled with translational motion. To elucidate the hydrodynamics of rotation, we analyzed the raptorial appendages of mantis shrimp (Stomatopoda) using a combination of flume experiments, mathematical modeling and phylogenetic comparative analyses. We found that computationally efficient blade-element models offered an accurate first-order approximation of drag, when compared with a more elaborate computational fluid-dynamic model. Taking advantage of this efficiency, we compared the hydrodynamics of the raptorial appendage in different species, including a newly measured spearing species, Coronis scolopendra The ultrafast appendages of a smasher species (Odontodactylus scyllarus) were an order of magnitude smaller, yet experienced values of drag-induced torque similar to those of a spearing species (Lysiosquillina maculata). The dactyl, a stabbing segment that can be opened at the distal end of the appendage, generated substantial additional drag in the smasher, but not in the spearer, which uses the segment to capture evasive prey. Phylogenetic comparative analyses revealed that larger mantis shrimp species strike more slowly, regardless of whether they smash or spear their prey. In summary, drag was minimally affected by shape, whereas size, speed and dactyl orientation dominated and differentiated the hydrodynamic forces across species and sizes. This study demonstrates the utility of simple mathematical modeling for comparative analyses and illustrates the multi-faceted consequences of drag during the evolutionary diversification of rotating appendages.


Subject(s)
Animal Structures/physiology , Decapoda/anatomy & histology , Decapoda/physiology , Hydrodynamics , Predatory Behavior/physiology , Rotation , Animals , Biomechanical Phenomena , Models, Biological , Movement , Species Specificity , Torque
5.
Interface Focus ; 6(3): 20150111, 2016 Jun 06.
Article in English | MEDLINE | ID: mdl-27274801

ABSTRACT

The use of high-speed puncture mechanics for prey capture has been documented across a wide range of organisms, including vertebrates, arthropods, molluscs and cnidarians. These examples span four phyla and seven orders of magnitude difference in size. The commonality of these puncture systems offers an opportunity to explore how organisms at different scales and with different materials, morphologies and kinematics perform the same basic function. However, there is currently no framework for combining kinematic performance with cutting mechanics in biological puncture systems. Our aim here is to establish this framework by examining the effects of size and velocity in a series of controlled ballistic puncture experiments. Arrows of identical shape but varying in mass and speed were shot into cubes of ballistic gelatine. Results from high-speed videography show that projectile velocity can alter how the target gel responds to cutting. Mixed models comparing kinematic variables and puncture patterns indicate that the kinetic energy of a projectile is a better predictor of penetration than either momentum or velocity. These results form a foundation for studying the effects of impact on biological puncture, opening the door for future work to explore the influence of morphology and material organization on high-speed cutting dynamics.

6.
Proc Biol Sci ; 282(1804): 20143088, 2015 Apr 07.
Article in English | MEDLINE | ID: mdl-25716791

ABSTRACT

A classic question in evolutionary biology is how form-function relationships promote or limit diversification. Mechanical metrics, such as kinematic transmission (KT) in linkage systems, are useful tools for examining the evolution of form and function in a comparative context. The convergence of disparate systems on equivalent metric values (mechanical equivalence) has been highlighted as a source of potential morphological diversity under the assumption that morphology can evolve with minimal impact on function. However, this assumption does not account for mechanical sensitivity-the sensitivity of the metric to morphological changes in individual components of a structure. We examined the diversification of a four-bar linkage system in mantis shrimp (Stomatopoda), and found evidence for both mechanical equivalence and differential mechanical sensitivity. KT exhibited variable correlations with individual linkage components, highlighting the components that influence KT evolution, and the components that are free to evolve independently from KT and thereby contribute to the observed pattern of mechanical equivalence. Determining the mechanical sensitivity in a system leads to a deeper understanding of both functional convergence and morphological diversification. This study illustrates the importance of multi-level analyses in delineating the factors that limit and promote diversification in form-function systems.


Subject(s)
Biological Evolution , Crustacea/anatomy & histology , Crustacea/physiology , Animals , Biomechanical Phenomena , Predatory Behavior
8.
J R Soc Interface ; 9(73): 1846-55, 2012 Aug 07.
Article in English | MEDLINE | ID: mdl-22399789

ABSTRACT

Computational models such as finite-element analysis offer biologists a means of exploring the structural mechanics of biological systems that cannot be directly observed. Validated against experimental data, a model can be manipulated to perform virtual experiments, testing variables that are hard to control in physical experiments. The relationship between tooth form and the ability to break down prey is key to understanding the evolution of dentition. Recent experimental work has quantified how tooth shape promotes fracture in biological materials. We present a validated finite-element model derived from physical compression experiments. The model shows close agreement with strain patterns observed in photoelastic test materials and reaction forces measured during these experiments. We use the model to measure strain energy within the test material when different tooth shapes are used. Results show that notched blades deform materials for less strain energy cost than straight blades, giving insights into the energetic relationship between tooth form and prey materials. We identify a hypothetical 'optimal' blade angle that minimizes strain energy costs and test alternative prey materials via virtual experiments. Using experimental data and computational models offers an integrative approach to understand the mechanics of tooth morphology.


Subject(s)
Computer Simulation , Models, Biological , Tooth/physiology , Animals , Biological Evolution , Humans , Tooth/physiopathology , Tooth Fractures/pathology , Tooth Fractures/physiopathology , Weight-Bearing
9.
Cancer Invest ; 23(7): 582-5, 2005.
Article in English | MEDLINE | ID: mdl-16305984

ABSTRACT

While it is important during treatment to flush the port-A-cath (PAC) with heparin regularly, catheter maintenance needs to be evaluated in those patients who, after completion of therapy, retained their ports for extended periods of time. The manufacturer has recommended monthly accession to maintain catheter patency and function. Our objective is to demonstrate that a longer interval between maintenance accessions of PACs still may be medically safe, convenient, and more efficient. We performed a retrospective review of all patients who had undergone PAC insertion from 1988 to 1993 at the Albert Einstein College of Medicine, and from 1997 to 2002 at the New York Hospital Medical Center of Queens. An adequate maintenance time is defined as a period of at least 6 months without chemotherapy or total parenteral nutrition. Data collected included date and location of PAC insertion, date of PAC accessions, PAC complications, and results of attempts at flushing the catheters with no venous blood return. All data were entered into an Excel spreadsheet and analyzed. The difference in interval accessions in patients without any complication to patients with complication was calculated using the Mann-Whitney "U" test. A total of 73 patients were included in the study. Compliance with visits for PAC maintenance varied considerably with the individual median accession times varying between 28 and 262 days with an overall median of 42 days. The individual means ranged from 29.5 to 244 days with an overall mean of 53.6 days. Seven patients in the group had episodes where the provider was unable to draw blood from the port during routine accession. The average intervals between accessions for each of these patients ranged from 38 to 244 days. The average intervals of accession among those patients who had no blood return during PAC accession was 79 days, versus 63 days for those without any difficulty. The difference was not statistically significant (p>0.05). Monthly maintenance of PAC is excessive, inconvenient for the patients, and expensive. Extending the interval of PAC maintenance proves to be medically safe and beneficial to the patients, the physicians and the health care system. Our clinical experience suggests that less frequent accessions of PACs is safe and feasible. We strongly advocate future prospective investigation of alternative PAC maintenance protocols in gynecologic cancer patients.


Subject(s)
Catheterization, Central Venous/adverse effects , Catheterization, Central Venous/methods , Catheters, Indwelling , Cost Control , Female , Genital Neoplasms, Female/drug therapy , Health Care Costs , Humans , Infection Control , Retrospective Studies , Safety , Time Factors
10.
Int J Gynecol Cancer ; 12(5): 459-64, 2002.
Article in English | MEDLINE | ID: mdl-12366663

ABSTRACT

The purpose of this study is to evaluate the toxicity and safety of concomitant cisplatin (CDDP) and extended field radiation therapy (EFRT) in patients with cervical cancer (CxCA) and endometrial cancer (EnCA). Twenty-five patients were analyzed retrospectively for treatment-related morbidity from 1989 to 1998. Fourteen patients had CxCA and 11 patients had EnCA. Eighteen patients (72%) had surgery prior to radiotherapy and chemotherapy. EFRT was delivered by a four-field technique to the pelvis and para-aortic regions. CDDP at 100 mg/m2 was given over 5 days during 1st and 4th week of EFRT. EFRT dose for EnCA and CxCA was 45 Gy. Toxicity was analyzed using the RTOG toxicity criteria. Twenty-four (96%) of the 25 patients completed the prescribed therapy. Of the 14 patients with CxCA, three (21%) had no toxicity, three (21%) had grade 1-2, and eight (58%) had grade 3-4 hematologic toxicities. Overall six (24%) had grade 3-4 acute gastrointestinal toxicities, three (21%) of these patients were treated for cervix cancer and three (27%) patients were treated for endometrial cancer. The worst (Grade 3-4) toxicities in 15 patients occurred after the 4th week of radiotherapy. In six of 25 (24%) patients radiation treatments had to be delayed due to toxicities. The median delay of treatment was 10.5 days (range 7-31 days). Of the six patients who had grade 3-4 acute gastrointestinal toxicities, four (66%) had undergone exploratory laparotomy and lymph node sampling prior to start of chemoradiation. We conclude that concomitant EFRT and CDDP appears to be safe with moderate but manageable toxicity. Toxicity is most severe after the 4th week of treatment. Morbidity may be worse in patients with prior laparotomy.


Subject(s)
Brachytherapy/methods , Cisplatin/administration & dosage , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/radiotherapy , Uterine Cervical Neoplasms/drug therapy , Uterine Cervical Neoplasms/radiotherapy , Adult , Aged , Aged, 80 and over , Brachytherapy/adverse effects , Chemotherapy, Adjuvant/adverse effects , Cisplatin/adverse effects , Combined Modality Therapy , Disease-Free Survival , Endometrial Neoplasms/mortality , Endometrial Neoplasms/surgery , Female , Humans , Hysterectomy/methods , Middle Aged , Prognosis , Radiotherapy, Adjuvant/adverse effects , Retrospective Studies , Risk Assessment , Sensitivity and Specificity , Survival Analysis , Treatment Outcome , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/surgery
11.
J Med Chem ; 43(10): 2019-30, 2000 May 18.
Article in English | MEDLINE | ID: mdl-10821714

ABSTRACT

A series of 4-alkenyl and 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC(90) = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses. The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5%, 2. 8%, and 0.2-0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.


Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Mutation , Quinazolines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Alkynes , Anti-HIV Agents/blood , Anti-HIV Agents/pharmacology , Benzoxazines , Blood Proteins/metabolism , Cyclopropanes , HIV-1/genetics , Humans , Molecular Structure , Oxazines/blood , Oxazines/pharmacology , Protein Binding , Quinazolines/blood , Quinazolines/pharmacology , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Virus Replication/drug effects
12.
Gynecol Oncol ; 76(1): 112-4, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10620451

ABSTRACT

We present a case of Stage I ovarian carcinoid tumor recurrent in the peritoneal cavity and review the pertinent literature concerning the management of this disease. Based on the data in the gynecologic and general surgery literature, it appears that primary complete cytoreductive surgery usually affords a high cure rate. Reexploration and attempt at complete resection of this slow-growing tumor appears to provide significant and prolonged palliation and is indicated for recurrent disease.


Subject(s)
Carcinoid Tumor/pathology , Neoplasm Recurrence, Local/surgery , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/pathology , Carcinoid Tumor/surgery , Female , Humans , Middle Aged , Ovarian Neoplasms/surgery , Palliative Care , Peritoneal Neoplasms/surgery , Prognosis
13.
Antimicrob Agents Chemother ; 43(12): 2893-7, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10582878

ABSTRACT

A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.


Subject(s)
Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , HIV-1/genetics , Mutation/physiology , Reverse Transcriptase Inhibitors/pharmacology , Amino Acid Substitution/genetics , Animals , Anti-HIV Agents/pharmacokinetics , Blood Proteins/metabolism , HIV-1/enzymology , Half-Life , Humans , Macaca mulatta , Male , Pan troglodytes , Protein Binding , Reverse Transcriptase Inhibitors/pharmacokinetics , Stereoisomerism
14.
Gynecol Oncol ; 74(2): 202-7, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10419732

ABSTRACT

OBJECTIVE: Several studies have demonstrated overexpression of the mononuclear phagocytic growth factor colony-stimulating factor-1 (CSF-1) and its receptor (CSF-1R) in breast, ovarian, and endometrial adenocarcinomas, and their expression in each of these cancers is strongly correlated with poor prognosis. In addition to adenocarcinomas, sarcomas that are highly malignant arise at much lower frequency in the uterus. Given the common organ of origin and hormonal environment of the adenocarcinomas, we evaluated the potential role of CSF-1 and CSF-1R in the genesis of these tumors using immunohistochemical methods. RESULTS: Immunohistochemical analysis was performed on 19 archival uterine sarcoma samples. Affinity-purified rabbit anti-CSF-1 antiserum (R52) and human cross-reactive murine anti-c-fms antibody were used. In the 19 cases evaluated for CSF-1 immunoreactivity, 42.1% had staining in less than 25% of the tumor, 36.9% had staining in 25-50% of the tumor, and only 21% had staining in greater than 50% of the tumor. When present, the majority of the CSF-1 immunostaining was associated with the extracellular matrix. There was variable intensity in CSF-1 expression: 52.6% had negative to mild staining, and 47.4% had moderate to strong staining. Immunostaining for the CSF-1R revealed that 52.6% of tumors had expression in less than 25% of cells, 21.0% had expression in 25-50% of the tumor, and 26.4% had staining in greater than 50% of the tumor. There was variable intensity of CSF-1R staining. Slight staining was found in 31.6% of the cases, moderate staining was found in 47.4% of the tumors, and 21.0% of the cases had strong expression. There was no statistically significant correlation between CSF-1 and CSF-1R expression and stage, estrogen/progesterone receptor status, number of mitoses per 10 high-power fields, or disease outcome. In addition, overall expression and intensity of CSF-1 and CSF-1R did not predict tumor virulence or disease outcome. CONCLUSION: In contradistinction to endometrial adenocarcinomas, in which CSF-1/CSF-1R is strongly correlated with tumor progression, CSF-1 and CSF-1R overexpression does not appear to play a role in the growth and differentiation of uterine sarcomas.


Subject(s)
Macrophage Colony-Stimulating Factor/physiology , Receptor, Macrophage Colony-Stimulating Factor/physiology , Sarcoma/etiology , Uterine Neoplasms/etiology , Female , Gene Expression Regulation, Neoplastic , Humans , Macrophage Colony-Stimulating Factor/analysis , Macrophage Colony-Stimulating Factor/biosynthesis , Receptor, Macrophage Colony-Stimulating Factor/analysis , Receptor, Macrophage Colony-Stimulating Factor/biosynthesis , Sarcoma/chemistry , Uterine Neoplasms/chemistry
15.
J Med Chem ; 42(7): 1178-92, 1999 Apr 08.
Article in English | MEDLINE | ID: mdl-10197962

ABSTRACT

Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.


Subject(s)
Isoxazoles/chemical synthesis , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Dogs , Humans , In Vitro Techniques , Injections, Intravenous , Isoxazoles/chemistry , Isoxazoles/metabolism , Isoxazoles/pharmacology , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/metabolism , Platelet Aggregation Inhibitors/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/metabolism , Sulfonamides/pharmacology , Time Factors
16.
J Womens Health ; 8(1): 103-7, 1999.
Article in English | MEDLINE | ID: mdl-10094087

ABSTRACT

To evaluate patient compliance with Papanicolaou (Pap) smear screening after tubal ligation compared with other methods of birth control in patients who develop cervical cancer, a retrospective review of 262 women with cervical cancer diagnosed at age < or = 70 years was undertaken at the Albert Einstein College of Medicine from January 1987 to December 1995. Demographic data, stage of the disease, histologic type, history of smoking, history of sexually transmitted disease (STD), and birth control use were recorded. The Pap screening history was obtained from all the patients. Women who had a bilateral tubal ligation (BTL) were compared with those who did not have this form of birth control. The date and result of their last Pap test prior to their diagnosis of cervical cancer was noted. Two hundred fourteen women with cervical cancer were evaluable. The clinical stage, mean age, history of smoking, and history of STD were similar for both groups. Gravidity among the BTL group was higher than in the non-BTL group (p < 0.01). Forty-eight (22.4%) women had a previous BTL. Twenty-seven of these 48 patients (56.3%) did not have a Pap smear within 3 years prior to the diagnosis of cervical cancer. Of the 166 patients, 61 (36.7%) did not have a Pap test within 3 years (p < 0.05). Fourteen women (29.2%) in the tubal ligation group never returned for a Pap test following the BTL. An average of 6.2+/-5.9 years elapsed since the last Pap test in the BTL group, with 4.0+/-5.1 years in the nontubal ligation group (p < 0.05). There was a correlation between the number of years since BTL (14.2+/-7.7) to the number of years since the last Pap test (6.2+/-5.9) (p < 0.05). Women who have had a BTL should be considered high risk because of poor screening compliance. A Pap test every 3 years is not adequate in this high-risk population group. We advocate improved counseling regarding the importance of continued annual Pap screening for women who are considering tubal ligation.


Subject(s)
Papanicolaou Test , Patient Compliance , Sterilization, Tubal/statistics & numerical data , Uterine Cervical Neoplasms/prevention & control , Vaginal Smears/statistics & numerical data , Adult , Aged , Female , Humans , Middle Aged , New York City , Odds Ratio , Retrospective Studies , Risk Factors
17.
Chem Biol ; 5(10): 597-608, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9818151

ABSTRACT

BACKGROUND: Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, however, to use HIV protease inhibitors in combination with other antiviral agents to inhibit the development of resistance. The daunting ability of the virus to rapidly generate resistant mutants suggests that there is an ongoing need for new HIV protease inhibitors with superior pharmacokinetic and efficacy profiles. In our attempts to design and select improved cyclic urea HIV protease inhibitors, we have simultaneously optimized potency, resistance profile, protein binding and oral bioavailability. RESULTS: We have discovered that nonsymmetrical cyclic ureas containing a 3-aminoindazole P2 group are potent inhibitors of HIV protease with excellent oral bioavailability. Furthermore, the 3-aminoindazole group forms four hydrogen bonds with the enzyme and imparts a good resistance profile. The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant--that containing the Ile84-->Val mutation. CONCLUSIONS: In selecting our next generation of cyclic urea HIV protease inhibitors, we established a rigorous set of criteria designed to maximize chances for a sustained antiviral effect in HIV-infected individuals. As DMP 850 and DMP 851 provide plasma levels of free drug that are sufficient to inhibit wild-type HIV and several mutant forms of HIV, they could show improved ability to decrease viral load for clinically significant time periods. The ultimate success of DMP 850 and DMP 851 in clinical trials might depend on achieving or exceeding the oral bioavailability seen in dog.


Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , Urea/analogs & derivatives , Animals , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Crystallography, X-Ray , Dogs , Drug Design , HIV/drug effects , HIV/genetics , HIV/physiology , HIV Protease Inhibitors/pharmacology , Molecular Structure , Mutation , Protein Binding , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacokinetics , Urea/pharmacology , Virus Replication/drug effects
18.
J Cardiovasc Pharmacol ; 32(2): 169-76, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9700976

ABSTRACT

This study was undertaken to define the platelet glycoprotein alphaIIb beta3 integrin (GPII/IIIa) affinity, specificity, and oral antiplatelet efficacy of DMP 802, a small-molecule nonpeptide antiplatelet agent. Platelet GPIIb/IIIa integrin binding affinity and specificity for DMP 802 were determined by using binding and adhesion assays with cells from various species, including human. DMP 802 demonstrated a potent antiplatelet efficacy [median inhibitory concentration (IC50), 0.029 +/- 0.0042 microM] in inhibiting human platelet aggregation induced by 10 microM adenosine diphosphate (ADP), as assessed by light-transmittance aggregometry. DMP 802 inhibited 125I-fibrinogen binding to activated (ADP, epinephrine, and arachidonic acid at 100 microM each) gel purified human platelets with an IC50 of 0.012 +/- 0.003 microM. DMP 802 demonstrated tight association with unactivated human, baboon, or canine platelets (t(1/2) of dissociation, 32 +/- 2, 32 +/- 13, and 11 +/- 1 min, respectively). DMP 802 binds with high affinity to both unactivated and activated human platelets (Kd = 0.61 +/- 0.17, 0.57 +/- 0.21 nM, respectively). DMP 802 demonstrated species specificity in inhibiting platelet aggregation with IC50 values ranging from 0.025 to 0.092 microM (human, guinea pig, dog, swine, hamster) and 0.88-1.0 microM (rabbit and rat) in platelets obtained from these various species. DMP 802 demonstrated a high degree of specificity for platelet GPIIb/IIIa (alphaIIb/beta3) as compared with other integrins including alpha(v)beta3 (IC50, >10 microM), alpha(v)beta5 (IC50, >100 microM), alpha4beta1 (IC50, >100 microM), and alpha5beta1 (IC50, >10 microM). Oral antiplatelet efficacy of DMP 802 was examined after single oral (0.05-0.20 mg/kg) and after repeated oral dosing at 0.05 mg/kg daily for 5 days in mongrel dogs. Dose-dependent antiplatelet efficacy with an extended duration of antiplatelet efficacy was demonstrated based on ex vivo inhibition of platelet aggregation induced by 100 microM ADP. DMP 802 has an oral bioavailability of 14.9% in dogs. In conclusion, the alpha sulfonamide isoxazoline analog, DMP 802, is a novel oral antiplatelet agent with high affinity, relatively slow dissociation rate and specificity for human platelet GPIIb/IIIa receptors.


Subject(s)
Isoxazoles/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Sulfonamides/pharmacology , Administration, Oral , Animals , Binding, Competitive , Blood Platelets/metabolism , Cell Adhesion/drug effects , Dogs , Enzyme-Linked Immunosorbent Assay , Female , Fibronectins/metabolism , Humans , Integrin alpha4beta1 , Integrins/metabolism , Male , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Rats , Receptors, Lymphocyte Homing/metabolism , Receptors, Vitronectin/metabolism , Vitronectin/metabolism
19.
Int J Radiat Oncol Biol Phys ; 38(1): 143-8, 1997 Apr 01.
Article in English | MEDLINE | ID: mdl-9212016

ABSTRACT

OBJECTIVE: Improved local control with the addition of brachytherapy to pelvic exenteration for recurrent cervical cancer has been reported to improve survival. We examined the sites of recurrence after pelvic exenteration to determine if these patients might have been salvaged by the improved local control promised by interstitial brachytherapy. We sought to identify risk factors available intraoperatively or perioperatively which might predict decreased local control. METHODS: A retrospective review of 26 patients with recurrent cervical cancer who underwent total pelvic exenteration since 1988 at our institution was performed. RESULTS: Overall, the mean follow-up was 29.5 months (range 6.1-81.6). Of the 26 patients, 14 had no evidence of disease (NED), 1 was alive with disease (AWD), 9 were dead of disease (DOD), and 2 died of unrelated causes (DOC). Seven of 26 patients (27%) had margins < or = 5 mm, of whom 2 were NED, 4 DOD, and 1 AWD. Seven of 26 (27%) patients had lymphovascular involvement (LVI) or perineural invasion (PNI) with clear margins. Three of the seven with LVI or PNI and clear margins were NED, and four DOD. Of the 10 failures, 9 (90%) had close margins, PNI, or LVI. CONCLUSION: Our data reveal that 9 of 14 (64%) patients with close margins, LVI, or PNI were DOD or AWD, and 6 of 9 of those patients suffered local regional failure alone. Brachytherapy has the potential to cure 6 of 14 (43%) patients with these risk factors. Further study of brachytherapy at the time of pelvic extenteration is warranted.


Subject(s)
Brachytherapy , Neoplasm Recurrence, Local/radiotherapy , Neoplasm Recurrence, Local/surgery , Pelvic Exenteration , Uterine Cervical Neoplasms/radiotherapy , Uterine Cervical Neoplasms/surgery , Adult , Aged , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Middle Aged , Neoplasm Recurrence, Local/mortality , Retrospective Studies , Uterine Cervical Neoplasms/mortality
20.
Disasters ; 21(4): 305-34, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9455005

ABSTRACT

This paper, the second in a series of state-of-the art reviews, examines the evolution and possible medium-term future of information technology (IT) in disaster management. Until the end of the 1970s, civilian application of IT to disaster management was confined to a few specialised departments of universities, large companies and government. Between the late 1970s and mid-1980s, microprocessor-based devices brought limited, though rapidly improving, computing capacity to a wider range of organisations and individuals. Operational applications included real-time emergency information, management decision support and programme and project planning. Extensive innovation occurred, though operational implementation was often long delayed or limited in scope. During the late 1980s, desktop systems became more powerful, more networked, more portable and generally more mature, with a range of practical emergency-related tools emerging. Computer communications emerged as a practical technology for linking emergency professionals on a global basis. From the early 1990s onwards, powerful and inter-connectable computer equipment has evolved to become an indispensable component of disaster operations worldwide. There are presently major changes under way in emergency-related global information access and networking--the implications of which have yet to be played out. The last part of the paper highlights a set of key technologies which seems likely to shape disaster planning, management and research over the next 10 years, and draws out some operational and organisational implications.


Subject(s)
Computer Communication Networks , Disaster Planning/organization & administration , Information Systems , Computer Communication Networks/history , Decision Support Techniques , Disaster Planning/history , Disaster Planning/trends , Forecasting , History, 20th Century , Humans , Information Storage and Retrieval/history , Information Storage and Retrieval/trends , Information Systems/history , Information Systems/trends
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