Improved Antiviral Activity of a Polyamide Against High-Risk Human Papillomavirus Via N-Terminal Guanidinium Substitution.

We report the synthesis of two novel pyrrole-imidazole polyamides with N-terminal guanidinium or tetramethylguanidinium groups and evaluate their antiviral activity against three cancer-causing human papillomavirus strains. Introduction of guanidinium improves antiviral activity when compared to an unsubstituted analog, especially in IC90 values. These substitutions change DNA-binding preferences, while binding affinity remains unchanged.

Necrobiosis lipoidica in a 9-year-old girl with new-onset type II diabetes mellitus.

Necrobiosis lipoidica (NL) is an idiopathic dermatologic condition that is strongly associated with, but not pathognomonic for, diabetes mellitus. It is more commonly seen in women than men and in adults than children. We present the youngest child, to our knowledge, diagnosed with NL at initial presentation with type II diabetes mellitus. We review the literature and discuss pathogenesis, clinical features, and treatment options for NL.

NMR spectroscopic investigations of mixed aggregates underlying highly enantioselective 1,2-additions of lithium cyclopropylacetylide to quinazolinones.

The solution structures of mixed aggregates derived from lithium alkoxides and lithium acetylides were investigated as part of a program to develop practical syntheses of quinazolinone-based nonnucleoside reverse transcriptase inhibitors. Low-temperature (6)Li, (13)C, and (15)N NMR spectroscopies reveal that mixtures of lithium cyclopropylacetylide (RCCLi), a (+)-carene-derived amino alkoxide (ROLi), and lithium hexamethyldisilazide (LiHMDS) in THF/pentane afford a (RCCLi)(3)(ROLi) mixed tetramer, a C(2)-symmetric and asymmetric (RCCLi)(2)(ROLi)(2) mixed tetramer, and a C(3)-symmetric (RCCLi)(ROLi)(3) mixed tetramer. Analogous mixtures of RCCLi/ROLi in Et(2)O and Me(2)NEt also provide 3:1, 2:2, and 1:3 mixed tetramers. The stereochemistry of aggregation is highly sensitive to the medium. The C(2)-symmetric (RCCLi)(2)(ROLi)(2) mixed tetramer is formed in Et(2)O, whereas the asymmetric isomer is formed in Me(2)NEt. LiHMDS in THF is shown to be an efficient proton scavenger without forming LiHMDS-RCCLi or LiHMDS-ROLi mixed aggregates. LiHMDS-RCCLi mixtures form mixed aggregates in Me(2)NEt.

The LPD-II: a modified locked percutaneous device that permits safe subcutaneous access.

A locked percutaneous device, the LPD-I (previously described as LPD), is effective in overcoming the problems of skin downgrowth and local tissue infection; however, it can only be implanted at a site providing adequate subcutaneous adipose tissue to attach to the subcutaneous connector of the LPD-I. A modified device, the LPD-II, has been developed that has a thin dome and skin connector but does not have a subcutaneous tissue connector. In addition, a newly designed structure called the skin stop collar (SSC) has been developed. It is positioned just beneath the mesh collar described in the LPD-I to further improve the function of the LPD-II. Six rabbits were implanted with one LPD-II without the SSC (group 1) and five rabbits were implanted with one LPD-II with the SSC (group 2). For more than 6 months, two of the implants in group 1 rabbits were successful. Four of the implants in group 2 rabbits were successful for more than 1 year. One of the animals in group 2 died of causes unrelated to the device. We conclude the following: the mesh collar skin connector can function well as a locked percutaneous device without the subcutaneous tissue connector; the LPD-II can be implanted in any site and does not require the presence of subcutaneous adipose tissue; and the SSC may increase the success rate of LPD-II implantation provided the mesh collar is made of soft material.

An efficient chiral moderator prepared from inexpensive (+)-3-carene: synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963.

The beta-amino alcohol 4 beta-morpholinocaran-3 alpha-ol is prepared by addition of morpholine to alpha-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.

Heart disease in children.

Advances in the understanding of the pathophysiology, diagnosis, and medical and surgical management of neonates with cardiovascular disease has led to their improved survival rates. These improvements have resulted in an increased number of pediatric patients presenting to the primary care physician's office with underlying heart disease. Understanding the genetic, congenital, or acquired etiologies to the various pediatric heart diseases is crucial to preventing these lesions and treating these patients.

Compiling the identifying features of bacterial endocarditis. Vague clues may point to this dangerous infection.

Bacterial endocarditis is a life-threatening disease. Before the advent of antibiotics, its mortality rate was nearly 100%, but with today's diagnostic and therapeutic advances, it can be successfully managed in most cases. In this article, Drs Harris and Steimle explain the changes that occur when someone, who usually has an underlying cardiac defect, contracts bacteremia with an organism likely to adhere to heart valve surfaces. They describe risk factors, clinical presentations, identification of causative organisms, and empirical and specific therapy. A case report illustrates the many possible manifestations of the disease.

A novel percutaneous barrier device that permits safe subcutaneous access.

Successful subcutaneous access is important for optimal management of internal artificial organs and treatment of many diseases. However, skin downgrowth and tissue infection are still significant problems in the use of devices that require long-term subcutaneous access. The authors developed a new percutaneous device that provides a unique biologic boundary with surrounding connective tissue while minimizing the risk of complications. This new percutaneous device is made of a circumferential, strong, thin, and flexible mesh collar with millimeter size holes for connecting the structure. It has two distinct functional portions: a connecting zone and a sealing line. The most important features of the structure are: 1) Connective tissue grows through the millimeter size pores of the connecting zone to form a strong bond between the device and healthy tissue. 2) The millimeter size pores of the connecting zone allow capillaries to grow through its entire surface, ensuring sufficient blood supply. 3) The tissue of the connecting zone and the device surface form a biosealed junction (sealing line). This sealing line is protected by the connecting zone and is free from external forces acting on local skin. 4) The device is generally functional immediately after surgical implantation. The subcutaneous perimeter of the functional dome contains extruded rigid rings of millimeter size holes permitting growth of subcutaneous tissue through the device. This functions as the minor connecting structure of the device. Four of five implanted rabbits have remained healthy 8 months postimplantation without antibiotic administration. The fifth rabbit died 4 months postimplantation for reasons unrelated to the device. Gross or histopathologic inspection revealed no signs of tissue injury or inflammation. Growth of healthy connective tissue was clearly observed. These results indicate this percutaneous device can provide a strong, stable, and effective connection to internal organs without bioboundary damage, skin downgrowth, or tissue infection.

The effect of an ambulatory internal medicine rotation on students' career choices.

PURPOSE: To assess the effect of an ambulatory care experience on medical students' perceptions of internal medicine and their choices of careers (as measured by residency selections). METHOD: In 1990-91, the 196 third-year students enrolled in the 12-week internal medicine clerkship at the University of Texas Medical School at San Antonio were randomized to a curriculum that included a three-week ambulatory care component or to a traditional, exclusively inpatient curriculum. The ambulatory curriculum included the evaluation of walk-in-patients, exposure to community internists, and a lecture series. The students' perceptions of internal medicine were surveyed before and after the clerkship. Their career choices were determined by their residency selections at graduation. Data analysis employed chi-square tests, t-tests, and logistic regression. RESULTS: Of the 196 students, 184 (76 in the ambulatory and 108 in the traditional curricula) provided complete data. The ambulatory care students were somewhat more likely to enter an internal medicine residency (odds ratio = 1.49; 95% CI, 0.72 to 3.09) than were the traditional students. The ambulatory care students' perceptions of internal medicine did not change significantly from before to after the clerkship. CONCLUSION: The ambulatory curriculum had a modest but favorable effect on the students' selections of careers in internal medicine, but was not associated with changes in their perceptions of internal medicine.

A multicenter prospective review of 640 endoscopic carpal tunnel releases using the transbursal and extrabursal chow techniques.

A prospective study involving eight institutions was performed, incorporating 640 cases of carpal tunnel release using a dual portal endoscopic technique. The original transbursal technique described by Chow was used in 110 cases (17%), and the modified extrabursal technique was used in 530 cases (83%). An overall complication rate of 11% was found in the patients in whom the transbursal technique was used, compared with 2.2% in the patients in whom the extrabursal technique was used. The return-to-work status was followed in 291 cases (199 non-worker's compensation cases and 92 worker's compensation cases). The worker's compensation patients returned to work in an average of 57 days, compared with 22 days for non-worker's compensation patients. This study suggests the extrabursal dual portal endoscopic technique is associated with fewer complications than the transbursal approach, and patients covered by worker's compensation return to work later than non-worker's compensation patients.

Maintaining normal intracranial pressure in a rabbit model during treatment of severe diabetic ketoacidemia.

Increased intracranial pressure (ICP) resulting in death or neurologic morbidity continues to complicate traditional management of diabetic ketoacidemia (DKA) in pediatric patients. When ICP or cerebrospinal fluid pressures have been measured, correction of hyperglycemia in animals and treatment of DKA in humans have consistently resulted in pathologic increases in ICP. We hypothesized that elevations in ICP can be minimized if changes in effective osmolality (Eosm) are controlled during treatment of DKA. During a six-hour study period, three groups of rabbits were studied: a normal control group of nondiabetic animals (Cnor, n = 10), a control group of animals with DKA (CDKA, n = 8), and an experimental group of animals with DKA (EDKA, n = 8). There was no significant difference between the two groups with DKA regarding pretreatment degree of dehydration, blood pressure, hyperglycemia, acidemia or ICP. During the treatment period, Cnor received maintenance fluids only. CDKA received insulin and an assumed volume of deficit (150 ml/kg) along with maintenance fluids and urinary output replacement with 0.45% NaCl. EDKA received insulin and one-half the volume of deficit calculated by the weight lost with 0.9% NaCl plus maintenance fluids. There was no significant difference between CDKA and EDKA regarding the rate at which DKA was corrected. While CDKA demonstrated a progressive and statistically significant increase in ICP, EDKA exhibited no such increase in ICP compared to normal, nondiabetic controls (Cnor) during treatment. Changes in Eosm during treatment in CDKA compared to Cnor and in CDKA compared to EDKA were significantly greater (p < .01), however, changes in EOSM in EDKA compared to Cnor were not significant. These data support the clinical observation that decreasing EOSM during treatment of DKA is associated with increased ICP and suggest that DKA can be treated effectively with i.v. fluids and insulin without increasing ICP.

Physiologic management of diabetic ketoacidemia. A 5-year prospective pediatric experience in 231 episodes.

OBJECTIVE: To determine whether gradual rehydration in moderate and severe diabetic ketoacidemia (DKA) can safely prevent untoward declines in calculated effective osmolality (Eosm) early in treatment and, hence, help prevent major central nervous system complications. DESIGN: Prospective study. SETTING: Three tertiary care hospitals. PATIENTS: Two hundred thirty-one consecutive episodes of DKA in 149 patients aged 10 months to 20 years admitted during a 5-year period. INTERVENTIONS: Insulin therapy in addition to rehydration using an estimated volume of deficit with planned administration over 48 hours; initial administration of rehydration solutions with an osmolality approximating that of the patient; and intensive patient monitoring. MEASUREMENTS: Mean lowest calculated Eosm (EosmL) during the first 24 hours of treatment; trend of the concentration of sodium in serum in the first 12 hours of treatment; comparison of pretreatment serum concentrations of glucose, urea nitrogen, and corrected sodium between mildly and very severely dehydrated patients; and patient outcome. RESULTS: A mean (+/- SD) EosmL of 285.8 +/- 10.5 mOsm/kg Nater and an increase in the concentration of sodium in serum in 90% of episodes were documented. There were statistically significant differences in serum concentrations of glucose, urea nitrogen, and corrected sodium in mildly vs very severely dehydrated patients. There were no deaths or near-death episodes. CONCLUSIONS: Management of moderate and severe DKA with a 48-hour planned rehydration is safe and prevents untoward declines in Eosm. Coupled with intensive monitoring, gradual rehydration can protect against life-threatening increases in intracranial pressure and brain herniation.

Correlation of primate red nucleus discharge with muscle activity during free-form arm movements.

1. We recorded from 239 neurons located in the magnocellular division of the red nucleus of four alert macaque monkeys. At the same time, we recorded electromyographic (EMG) signals from as many as twenty electrodes chronically implanted on muscles of the shoulder, arm, forearm and hand. We recorded EMG signals for periods ranging from several months to a year. 2. The monkeys were trained to perform three free-form food retrieval tasks, each of which activated all of the recorded muscles and most of the neurons. The 'prehension' task required simply that the monkey grasp a piece of food from a fixed point in space. The 'barrier' task required the monkey to reach around a small barrier to obtain the food, and the 'Kluver' task required that food be removed from small holes. During the prehension task, we found approximately equal numbers of neurons that were strongly active while the hand was being moved toward the target (70% of units), and while the food was being grasped (60%). Relatively few units were active as the hand was returned to the mouth (15%). 3. Data files of 1-2 min duration were collected while the monkey performed a single behavioural task. Whenever possible, we recorded files for all three tasks from each neuron. For each file we calculated long time-span analog cross-correlations (+/- 1.28 s) between instantaneous neuronal firing rate and each of the full-wave rectified, low-pass filtered EMG signals. We used the peak correlation and the time of the peak as two summary measures of the functional relation between modulation of neuronal activity and EMG. 4. The magnitude of the strongest correlations was between 0.4 and 0.5 (normalized to a perfect correlation of +/- 1.0). Distal muscles were the most frequently correlated, and extensors were more frequently correlated than flexors. For all monkeys, the lags for well correlated muscles were distributed broadly about a uni-modal value near 0 ms. Eighty five per cent of the correlations larger than or equal to 0.25 had peaks between -150 and 200 ms. 5. The activity of each neuron was represented in a muscle co-ordinate system by an n-dimensional 'functional linkage vector', each element of which was the peak correlation with one of n muscles. The vector for any given neuron points in a particular direction in muscle space, depending on the similarity between the activity of the neuron and the activity of each muscle.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain osmoregulation during extreme and moderate dehydration in a rat model of severe DKA.

To determine if osmoprotective molecules accumulate in the brain during severe DKA with extreme (DKA-E) and moderate (DKA-M) dehydration, Fischer 344 rats (250-350g) were given STZ 45 mg/kg (i.p.) and allowed food and water ad lib. DKA-M received NaCl 77 mmol/L 60 ml/kg (i.p.) q 4 hrs. on day 2. All rats were anesthetized and sacrificed at 48 hrs. Half of each brain was used to measure water content (BWC) and half to measure Na+, K+, and organic osmoles by HPLC. Just prior to expiration, values for mean concentration of serum glucose (mmol/L) percent weight loss and median blood pH for DKA-E were 33.4, 19%, 6.98; for DKA-M, 16.8, 7.5% and 6.84, respectively. Means +/- SEM were compared by Student's t-test. Percent BWC was 76.3, 77.3 and 77.6 in DKA-E, DKA-M and normal controls, respectively (NS). Brain Na+ and K+ were increased in DKA-M compared to controls (p < .05) but not significantly different in DKA-E compared to controls. Of organic osmoles measured (umol/g wet weight) taurine was significantly increased (p < .01) in DKA-E and DKA-M (8.04 +/- .39 and 9.73 +/- .78, respectively) as compared to controls (5.92 +/- .35) as was myoinositol in DKA-E compared to controls (9.96 +/- .39 vs. 8.87 +/- .28) (p < .05) and urea in DKA-E as compared to controls (14.24 +/- 3.9 vs. 4.14 +/- .52) (p < .01). DKA-M were not significantly different for brain myoinositol or urea as compared to control animals. There was no significant difference in brain glutamine between either study group and controls. Preservation of brain water despite systemic dehydration can be partly explained by increased brain concentrations of osmoprotective molecules. Such adaption in the clinical setting of DKA warrants a cautious repair of dehydration and hyperosmolality.