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Results for “virtual intervention”

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PubMed1994

Educational visiting and hypnosedative prescribing in general practice.

Public concern about the prescription of hypnosedative drugs (mostly benzodiazepines) led to a controlled trial of an educational intervention to promote rational prescribing by general practitioners (GPs). This paper describes the educational intervention and its process evaluation. In urban and rural New South Wales 137 GPs were visited in office hours by a GP or pharmacist who had undergone communication skills training. Material offered to GPs included relaxation tapes and a booklet of problem-orientated management guidelines. The interview had three stages: rapport was established, then educational material was introduced and finally the visitor sought the doctor's agreement to review five patients on long-term benzodiazepines. The visits were well received. Several measures were composed to reflect doctors' motivation and interest in non-drug management; there was virtually no correlation between any of these process measures and the trial outcome: a change in prescribing behaviour. Self-rating of benzodiazepine prescribing greatly underestimated actual self-reported incidents of prescribing. We interpret this as a reminder that we do not always do what we mean to do, and that we do not always do what we think we do.

Anti-Anxiety Agents↗

PubMed1999

Effect of modified dairy fat on fasting and postprandial haemostatic variables in healthy young men.

It has been suggested that milk fat, due to its content of saturated fatty acids, may have a thrombogenic effect. In the present study the fatty acid profile of milk fat was modified by changing the feeding regimens of cows and the effect on haemostatic variables of a diet containing the modified milk fat (M) was compared with that of a diet containing milk fat of typical Danish composition (D). In the modified fat 16% of the saturated fatty acid (C12-C16) content was replaced mainly by oleic acid. Eighteen subjects were fed on two strictly controlled isoenergetic diets containing 40% energy from total fat (30% energy from the test fats) for periods of 4 weeks in a study with a crossover design. Fasting samples were taken in the last week of each study period. Postprandial samples were taken on day 21, 3 h after lunch (n 18), and on the last day of the study 2, 4, 6 and 8 h after a fat load containing 1.2 g of one of the milk fats/kg body weight (n 8). After 4 weeks' dietary intervention fasting plasma factor VII coagulant (FVIIc) activity, tissue-type plasminogen activator (t-PA) activity, plasminogen activator inhibitor (PAI-1) antigen and beta-thromboglobulin did not differ between diets M and D. Postprandially FVIIc and t-PA activities increased (P < 0.001) and PAI-1 antigen and PAI-1 activity decreased (P < 0.001) as compared with fasting values, regardless of diet. After the fat load, the postprandial increase in FVIIc was marginally lower after diet M than diet D (diet effect, P < 0.05). In conclusion, the modified milk fat obtained by the applied feeding strategy had virtually the same effects on haemostatic variables as conventional milk fat.

Adult↗

PubMed1980

Stereotyped behaviour, alternative behaviour and collateral effects: a comparison of four intervention procedures.

The effects of four procedures (i.e. a mild slap to the forearm, differential reinforcement of an alternative behaviour (DRA), overcorrection plus DRA, and a mild slap plus DRA), on a sterotyped behaviour, an alternative behaviour, and collateral self-injurious behaviours of a profoundly retarded five-year-old girl were assessed in a modified multiple baseline, reversal design. A mild slap resulted in rapid suppression of target and nontarget behaviours. During DRA, a slight increase was achieved in the target behaviour. However, no suppression of the other behaviours were evidenced. Overcorrection plus DRA proved relatively ineffective both in suppressing the target stereotyped behaviours and in accelerating the alternative behaviour. The most effective procedure was mild slap plus DRA. Near zero suppression of the stereotyped behaviour was attained on the first day of implementation, collateral self-injurious behaviours were virtually eliminated, and alternative behaviour increased dramatically. There was some evidence for generalisation across trainers, settings, and time.

Behavior Therapy↗

PubMed2004

Hormonal counterregulation during severe hypoglycaemia under everyday conditions in patients with type 1 and insulin-treated type 2 diabetes mellitus.

AIM: To determine the counterregulatory hormonal responses to severe hypoglycaemia (SH) in type 1 versus insulin-treated type 2 diabetic patients under everyday conditions. METHODS: Counterregulatory hormones were determined in 28 consecutive type 1 and thirteen insulin-treated type 2 diabetic patients (age 54 +/- 18 vs. 75 +/- 13 yrs; diabetes duration 27 +/- 16 vs. 21 +/- 6 yrs) with SH requiring emergency treatment. Blood samples were taken prior to and after effective treatment of SH. SH was defined as an event with neuroglycopenic presentation requiring external intervention by administration of intravenous glucose or oral carbohydrates. 68 % (19/28) of type 1 diabetic patients but none of those with type 2 diabetes had reduced awareness of hypoglycaemia. RESULTS: Plasma glucose levels were 30 +/- 14 prior to and 179 +/- 82 mg/dl after treatment of SH; the time between the two measurements was 54 +/- 26 minutes. With the exception of higher levels of human growth hormone in type 1 patients - which were attributed to younger age - the other counterregulatory responses to SH showed no significant differences in type 1 vs. type 2 diabetic patients. In both groups glucagon responses were virtually absent while moderate catecholamine responses could be demonstrated. Treatment with beta-blockers did not affect hormonal counterregulation in type 1 diabetic patients. CONCLUSIONS: In patients approaching the insulin-deficient end of the spectrum of type 2 diabetes the hormonal responses to SH are comparable to those in patients with longstanding type 1 diabetes. Thus, in advanced type 2 diabetes the risk of developing SH may be similar to that in individuals with type 1 diabetes.

Adolescent↗

PubMed2004

Effects of sleep deprivation on spontaneous arousals in humans.

STUDY OBJECTIVES: The hierarchical definition of arousals from sleep includes a range of physiologic responses including microarousals, delta and K-complex bursts, and variations in autonomic system. Whether patterns in slow-wave electroencephalographic activity and autonomic activation are primary forms of arousal response can be addressed by studying effects of total sleep deprivation. We therefore examined changes in arousal density during recovery sleep in healthy subjects. DESIGN: Participants spent 6 consecutive 24-hour periods in the laboratory. Nights 1 and 2 were baseline nights followed by 64-hour total sleep deprivation, then 2 consecutive recovery nights. SETTING: Sleep-deprivation protocol was conducted under laboratory conditions with continuous behavioral and electrophysiologic monitoring. PARTICIPANTS: Twelve drug-free men aged 27.4 +/- 7.9 years were studied. None reported sleepiness or altered sleep-wake cycle, and none had neurologic, psychiatric or sleep disorders. INTERVENTION: N/A. MEASUREMENTS AND RESULTS: Arousals were classified into 4 levels: microarousals, phases of transitory activation, and delta and K-complex bursts. Sleep deprivation induced changes in the density of considered arousals except phases of transitory activation, with a distinct pattern among the different types. The greatest change was found for microarousals, which showed a significant decrease in the first recovery night (P = .01), with return to baseline thereafter. A fall in K-complex and delta-burst density was noted in the first recovery night, not, however, reaching statistical significance. The phases of transitory activation rate were virtually unaffected throughout the experimental nights. CONCLUSIONS: We conclude that homeostatic sleep processes exert an inhibitory effect on arousal response from sleep with a significant effect only on the microarousal density. Decreased delta and K-complex burst rates, though not significant, support the hypothesis that they may be activating processes, probably modulated by factors independent from those implicated in cortical arousal.

Adult↗

PubMed2001

Fine-needle aspiration biopsy.

OBJECTIVES: Fine-needle aspiration biopsy (FNAB) is a technique in which a fine needle is introduced into a mass, cellular material is aspirated, and a cytological diagnosis is rendered. It separates reactive and inflammatory processes that do not require surgical intervention from neoplasia and benign from malignant tumors. FNAB lends itself to the diagnosis of palpable head and neck masses, in particular, those that persist following antibiotic treatment. STUDY DESIGN/METHODS: This clinical state-of-the-art review article is intended to provide an overview of the clinical use of FNAB in the management of head and neck masses. Relevant case histories are used to illustrate this point. RESULTS: Fine-needle aspiration biopsy has a high overall diagnostic accuracy of 95% for all head and neck masses, 95% for benign lesions, and 87% for malignant ones. CONCLUSIONS: There are virtually no contraindications, and complications are minimal. Advantages of FNAB are that it is safe and simple, it can be performed as an outpatient procedure, and it is well tolerated by patients. In the present managed care environment, it also proves cost-effective. The diagnosis is readily known to the clinician, and appropriate treatment modalities can be discussed with the patient. It is recommended as a first line of investigation in palpable head and neck masses.

Adult↗

PubMed1996

Application of USAF G-suit technology for clinical orthostatic hypotension: a case study.

INTRODUCTION: The purpose of this study was to determine the effectiveness of a USAF anti-gravity suit (G-suit) on the stability of a patient with chronic orthostatic hypotension. METHODS: A 37-yr-old female with a history of insulin-dependent diabetes mellitus (IDDM) and symptomatic orthostasis was evaluated and the results were compared with those of non-diabetic controls, matched for age, height, and weight. Cardiac vagal tone was assessed by determination of standard deviation of 100 R-R intervals (R-R SD). We assessed the carotid-cardiac baroreflex response by plotting R-R intervals (ms) at each of eight neck pressure steps with their respective carotid distending pressures (mm Hg). Heart rate and blood pressure were recorded in response to the Valsalva maneuver (VM) performed at an expiratory pressure of 30 mmHg to assess integrated baroreflex responses. Blood pressures and heart rate were measured during three 5-min stand tests to assess orthostatic responses: a) without G-suit; b) with noninflated G-suit; and c) with inflated G-suit (50 mm Hg). RESULTS: The IDDM patient had minimal baseline cardiac vagal tone (R-R SD = 8.5 ms) compared with the average response of a control group of 24 subjects with orthostatic stability (R-R SD = 67.2 +/- 7.1 ms). Carotid-cardiac baroreflex response was virtually non-existent in the IDDM patient (Gain = 0.06 ms.mm Hg-1) compared to the control subjects (4.4 +/- 0.8 ms.mm Hg-1). VM responses corroborated the lack of cardiac baroreflex response in the IDDM patient, while blood pressure changes during the VM were similar to those of the controls. Upon standing, the IDDM patient demonstrated severe orthostatic hypotension (90 mm Hg SBP) and tachycardia without the G-suit. The G-suit, with and without pressure, reduced hypotension and tachycardia during standing. CONCLUSION: These results demonstrate successful application of Air Force technology as a useful alternative to pharmacologic intervention in the treatment of a patient with autonomic dysfunction leading to supine hypertension and orthostatic hypotension.

Adult↗

PubMed1998

Protecting fetuses from certain harm.

Deborah Mathieu's proposal for state intervention in the lives of pregnant substance abusers in order to prevent serious harm to their future children sparked a lively debate in this journal. The present discussion characterizes the three main arguments offered against her proposal as (a) the "uncertainty principle"--the inability to predict which fetuses will be affected, (b) the "father factor"--gender bias with respect to prenatal damage, and (c) "critical periods"--the vulnerability of the embryo/fetus at different times of pregnancy. Each of these arguments is examined in the specific context of fetal alcohol syndrome (FAS). Since the birth of a child with FAS is a virtual certainty if a woman has previously given birth to a child with FAS, since no father has ever sired a child with FAS unless his spouse is an alcoholic, and since the most damaging effects are those associated with exposure throughout and especially late in pregnancy, none of the arguments offered against Mathieu's proposal are relevant in this particularly narrow set of circumstances. While Mathieu's proposal seems pertinent in this situation, her proposal would be even more effective if modified as suggested here.

Child↗

PubMed2001

New developments in anti-HIV chemotherapy.

Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e., zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir (PMPA) disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine (MKC-442); and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease step, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polyoxometalates, zintevir, negatively charged albumins, cosalane analogues); (ii) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5 [bicyclams (i.e. AMD3100), polyphemusins (T22), TAK-779, MIP-1 alpha LD78 beta isoform]; (iii) virus-cell fusion, through binding to the viral glycoprotein gp41 [T-20 (DP-178), T-1249 (DP-107), siamycins, betulinic acid derivatives]; (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA) and NCp7 peptide mimics]; (v) proviral DNA integration, through integrase inhibitors such as L-chicoric acid and diketo acids (i.e. L-731,988); (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (fluoroquinolone K-12, Streptomyces product EM2487, temacrazine, CGP64222). Also, in recent years new NRTIs, NNRTIs and PIs have been developed that possess respectively improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides of d4T), or increased activity against NNRTI-resistant HIV strains [second generation NNRTIs, such as capravirine and the novel quinoxaline, quinazolinone, phenylethylthiazolylthiourea (PETT) and emivirine (MKC-442) analogues], or, as in the case of PIs, a different, non-peptidic scaffold [i.e. cyclic urea (DMP 450), 4-hydroxy-2-pyrone (tipranavir)]. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cell-free enzymatic assays to the mode of action of these agents in intact cells. A number of compounds (i.e. zintevir and L-chicoric acid, on the one hand; and CGP64222 on the other hand) have recently been found to interact with virus-cell binding and viral entry in contrast to their proposed modes of action targeted at the integrase and transactivation process, respectively.

Amino Acid Sequence↗

PubMed2005

An evaluation of a colour food photography atlas as a tool for quantifying food portion size in epidemiological dietary surveys.

OBJECTIVE: To test the validity of a colour food photography atlas for quantifying portion size eaten compared with weighed foods. DESIGN: The colour food photography atlas was prepared by cooking, weighing and taking digital photographs of three portion sizes of 434 foods and beverages typical of the Italian diet. SUBJECTS AND INTERVENTIONS: In all, 448 male and female volunteers aged 6-60 y from a wide variety of social backgrounds completed 9075 assessments of food portions eaten at lunch and dinner in relation to a set of colour food photographs during 8 weeks of investigation. The amounts of foods eaten by individuals in five different cafeterias in Pavia, Northern Italy, were weighed by trained investigators at the time of serving and, within 5-10 min of the end of the meal, each subject was asked to quantify all foods consumed with reference to one of the three food photographs or in terms of virtual portions among those shown in the photographs. RESULTS: Multiple regression analysis shows that weights of portion sizes chosen from the set of photographs are significantly associated (P<0.05) to weights of eaten portions (beta=0.81; R(2)=0.70) and are independent of age, gender and BMI. The differences between mean weights of the portions chosen by individuals from photographs and mean weights of eaten foods are significant for all food categories (P<0.05), except for bread. However, because of the very large number of observations, the mean differences are very small (range: from +23.2 g (+11.2%) for first courses to -1.3 g (-2.7%) for bread). Bland-Altman plots show that first courses limits of agreement are wide because the dispersion is increasing while weights are rising. CONCLUSIONS: The use of a series of three photographs and virtual portion sizes being associated with relatively small errors, our findings support the validity of using this colour food photography atlas as a tool for quantifying food portion size in epidemiological dietary surveys on different age groups of Italian subjects.

Adolescent↗

PubMed2003

Lower extremity stepping-table magnetic resonance angiography with multilevel contrast timing and segmented contrast infusion.

OBJECTIVES: Standard lower extremity contrast-enhanced magnetic resonance angiography (LE-CEMRA) with single injection bolus-chase methods on the basis of a single pelvis timing run can be accurate for depicting most vascular occlusive lesions but may fall short of catheter-based angiography when imaging tibial and pedal vessels. Magnetic resonance angiography techniques with a second contrast timing bolus and separate acquisitions for the calves and the pelvis greatly improve reliability and reduce venous contamination to levels that may render conventional angiography obsolete. METHODS: From July to December 2001, 60 consecutive patients underwent LE-CEMRA of the calves with separate stepping-table acquisitions of the pelvis and thighs. Forty-five (75%) had complete or partial angiographic correlation during an endoluminal intervention or operative completion study. Lower extremity vessels were divided into anatomic segments (aortoiliac, femoropopliteal, tibial-pedal) for review. Three blinded observers assessed magnetic resonance source partitions, maximum-intensity projections, and volume-rendered images. Disease per segment was graded from insignificant (<20%) to occluded (100%) in 10% increments. Segments were also scored for venous contamination (scale, 0 to 3) and diagnostic quality (scale, 1 to 5). Digital subtraction angiograms were assessed similarly but separately. RESULTS: The combination dual-timing/dual-injection technique had an overall sensitivity, specificity, and accuracy of 99%, 97%, and 98%. Venous contamination and artifact were virtually eliminated with combined technique LE-CEMRA. Diagnostic quality of calf and foot vessels was significantly superior to conventional bolus-chase magnetic resonance techniques (P <.01). CONCLUSION: Hybrid dual-acquisition LE-CEMRA allows complete timing specification that consistently produces high-quality, artifact-free images of the calf and pedal vessels. These techniques may be accurate enough to replace conventional digital subtraction angiogram for evaluation of lower extremity vascular occlusive disease.

Adult↗

PubMed2001

Lymphocyte-mediated cytotoxicity.

Virtually all of the measurable cell-mediated cytotoxicity delivered by cytotoxic T lymphocytes and natural killer cells comes from either the granule exocytosis pathway or the Fas pathway. The granule exocytosis pathway utilizes perforin to traffic the granzymes to appropriate locations in target cells, where they cleave critical substrates that initiate DNA fragmentation and apoptosis; granzymes A and B induce death via alternate, nonoverlapping pathways. The Fas/FasL system is responsible for activation-induced cell death but also plays an important role in lymphocyte-mediated killing under certain circumstances. The interplay between these two cytotoxic systems provides opportunities for therapeutic interventions to control autoimmune diseases and graft vs. host disease, but oversuppression of these pathways may also lead to increased viral susceptibility and/or decreased tumor cell killing.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Properties of the 40 kDa antigen of Mycobacterium tuberculosis, a functional L-alanine dehydrogenase.

The 40 kDa antigen of Mycobacterium tuberculosis is the first antigen reported to be present in the pathogenic M. tuberculosis, but not in the vaccine strain Mycobacterium bovis BCG. It is a functional L-alanine dehydrogenase (EC 1.4.1.1) and hence one of the few antigens possessing an enzymic activity. This makes the 40 kDa antigen attractive for potential diagnostic and therapeutic interventions. Recently, we developed a strategy to purify quantities of the recombinant protein in active form, and here we describe the biochemical properties of this enzyme. In the oxidative-deamination reaction, the enzyme showed K(m) values of 13. 8 mM and 0.31 mM for L-alanine and NAD(+), respectively, in a random-ordered mechanism. K(m, app) values in the reductive-amination reaction are 35.4 mM, 1.45 mM and 98.2 microM for ammonium, pyruvate and NADH, respectively. The enzyme is highly specific for all of its substrates in both directions. The pH profile indicates that oxidative deamination virtually may not occur at physiological pH. Hence L-alanine most likely is the product of the reaction catalysed in vivo. The enzyme is heat-stable, losing practically no activity at 60 degrees C for several hours.

Alanine Dehydrogenase↗

PubMedDate not supplied

[The role of endoscopic ultrasound in digestive tract diseases in era of advanced techniques of computed tomography].

During the last 20 years endoscopic ultrasound (EUS) has been established as a highly accurate method in the diagnosis of digestive tract diseases. This method enables analysis of the lesions within the bowel wall, pancreas, and biliary system with utmost precision. Good results have also been achieved in evaluation of regional lymphadenopathy in staging of malignant diseases. Principal limitations of this method originate from its low accesibility and technical complexity which requires well trained sinologist and scientific evaluation of results in order to achieve adequate level of skill. Complications occur rarely with numbers comparable to other endoscopic procedures. With new software and hardware device introduced, computerized tomography (CT) (this refers in the first place to multidetector row CT) has been tremendously upgraded approaching the EUS in diagnostic accuracy in mentioned indications, and overcoming it in detection of distant metastases. Implementation of 3D reconstruction techniques allowed CT to enter the area of classic endoscopy, as in the case of virtual gastroscopy and/or colonoscopy. CT is a noninvasive method, very acceptable to majority of patients, and therefore popular and more prevalent compared to EUS. Although comparable in diagnostic accuracy in majority of indications, endosonography retains advance in evaluation of lesions within GI tract wall (including the early stages of carcinoma), detection of small biliary stones and small pancreatic tumors. Moreover, EUS is indespensable in therapeutic indications. Experiences with fine needle aspiration, punctions and drainage of cysts and abscesses, celiac plexus neurolysis and creation of digestive anastomosis confirm its place and value among the minimally invasive procedures which minimize the need for surgical intervention, patients' trauma and treatment costs.

Digestive System Diseases↗

PubMed1993

Comparison of the sacral base angle in females with and without spondylolysis.

OBJECTIVE: The aim of this study was to determine if there was a difference in the sacral base angle in females with spondylolysis compared with females without spondylolysis. This is a follow-up study to an earlier pilot program, in which the female sample size was too small. DESIGN: Retrospective study utilizing upright neutral lateral lumbar radiographs of females with evidence of pars defects (test group) and upright neutral lateral radiographs of females with no evidence of pars defects (control group). The control group was age matched to the test group. SETTING: Chiropractic college clinic. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The sacral base angle was measured on each radiograph. RESULTS: The mean sacral base angle was found to be 52.7 +/- 6.8 degrees (mean +/- SD) (n = 22) and 38.6 +/- 7.6 degrees (mean +/- SD) (n = 47) in the test and control groups respectively. This difference was found to be statistically significant (p < .001). CONCLUSIONS: The study has determined that females with spondylolysis have a steeper sacral base angle than females without spondylolysis. It does not, however, indicate whether a larger sacral base angle is a cause or an effect of the spondylolysis. This study also suggests that there is virtually no difference in the sacral base angles between males and females with and without pars defects.

Female↗

PubMed2002

Temporal trends in femoral curvature and length in medieval and modern Scotland.

We measured how much the radius of the anterior curvature and the length of the femoral shaft of cadaveric bones have changed from medieval to recent times. Around 20 (x, y) coordinates of a virtual coordinate system were measured at intervals of 1.5 cm along the shaft of the femur to calculate one single radius of a virtual circle in the (x, y) plane. The median radii of curvature were 119, 141, and 158 cm for medieval, early, and late 20th century femora, respectively. Early and late 20th century femora were of similar length (45 cm), but medieval femora were shorter (43.5 cm). Femora have become not only longer but also straighter since the Middle Ages. These findings account in part for the increase in height of modern generations. Size and shape changes may have significant implications for the biomechanical response of the femur to the forces to which it is subjected in everyday life, in trauma, and following surgical intervention.

Anthropology, Physical↗

PubMed2002

New anti-HIV agents and targets.

Virtually all the compounds that are currently used or are subject of advanced clinical trials for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside reverse transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine and nucleotide reverse transcriptase inhibitors (NtRTIs) (i.e., tenofovir disoproxil fumarate); (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine; and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polycarboxylates, polyoxometalates, polynucleotides, and negatively charged albumins); (ii) viral entry, through blockade of the viral coreceptors CXCR4 (i.e., bicyclam (AMD3100) derivatives) and CCR5 (i.e., TAK-779 derivatives); (iii) virus-cell fusion, through binding to the viral envelope glycoprotein gp41 (T-20, T-1249); (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA)]; (v) proviral DNA integration, through integrase inhibitors such as 4-aryl-2,4-dioxobutanoic acid derivatives; (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (flavopiridol, fluoroquinolones). Also, various new NRTIs, NNRTIs, and PIs have been developed that possess, respectively: (i) improved metabolic characteristics (i.e., phosphoramidate and cyclosaligenyl pronucleotides by-passing the first phosphorylation step of the NRTIs), (ii) increased activity ["second" or "third" generation NNRTIs ( i.e., TMC-125, DPC-083)] against those HIV strains that are resistant to the "first" generation NNRTIs, or (iii), as in the case of PIs, a different, modified peptidic (i.e., azapeptidic (atazanavir)) or non-peptidic scaffold (i.e., cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)). Non-peptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs.

Amino Acid Sequence↗

PubMed2003

Estrogen deposits extra mineral into bones of female rats in puberty, but simultaneously seems to suppress the responsiveness of female skeleton to mechanical loading.

To first test the possible effect of gender on the responsiveness of growing rat skeleton to mechanical loading, 5-week-old littermates of 25 male and 25 female rats were subjected to either free-cage activity or treadmill training for a period of 14 weeks (experiment 1). Using peripheral quantitative computed tomography (pQCT) and mechanical testing of the femoral neck, we observed female rats exhibiting a clearly lower responsiveness to external loading than male rats (+3.0% vs +25% in cross-sectional area (CSA), +4.2% vs +27% in the bone mineral content (BMC), -0.6% vs +10% in volumetric bone mineral density (BMD), and +4.7% vs +28% in fracture strength (F(max)) of the femoral neck). Also, relative to the mechanical demands placed on the skeleton, the bones of the young female rats were considerably denser (>50%) than those of the males. In the subsequent experiment 2, we repeated the above-noted first experiment with 33-week-old rats and observed virtually identical exercise-induced benefits (+2.1% vs +10% in CSA, +3.4% vs +18% in BMC, +2.5% vs +23% in BMD, and -1.1% vs +27% in F(max) in females vs males, respectively) and the growth/puberty-related condensation of mineral into female bones. Finally, in experiment 3, 60 littermates of 3-week-old female rats were first subjected to sham operation or ovariectomy and then further randomized to exercise or control groups, respectively, to study whether the condensation of mineral into female bones and their lower responsiveness to loading were attributable to the effects of estrogen. At the end of the 16-week intervention, our pQCT and mechanical testing analysis showed not only the anticipated effect of reduced bone density in the ovariectomized rats ( approximately -20%) but also the hypothesized better responsiveness to mechanical loading in these estrogen-depleted rats (-3.5% vs +9.1% in CSA, -0.4% vs +12% in BMC, +4.4% vs +9.6% in BMD, and -4.2% vs +16% in F(max) in SHAM vs OVX, respectively). In conclusion, the results of our series of three experiments suggest that as such estrogen seems to have very little primary effect on the sensitivity of female bone to respond to external loading, but rather deposits extra stock of mineral into female bones in puberty. This estrogen-driven extra condensation of the female skeleton seems to persist into adulthood, simultaneously damping the responsiveness of the female skeleton to mechanical loading.

Animals↗