Innovative Clinical Scenario Simulator for Step-by-Step Microsurgical Training.

BACKGROUND: Microsurgical training should be implemented with consideration of operative difficulties that occur in actual clinical situations. We evaluated the effectiveness of a novel clinical scenario simulator for step-by-step microsurgical training that progressed from conventional training to escalated training with additional obstacles. METHODS: A training device was designed according to multiple and intricate clinical microsurgery scenarios. Twenty surgical residents with no experience in microsurgery were randomly assigned to either the control group (conventional training curricula, n = 10) or the experimental group (step-by-step training courses, n = 10). After 4 weeks of laboratory practice, the participants were scheduled to perform their first microvascular anastomoses on patients in an operating room. The Global Rating Scale (GRS) scores and operative duration were used to compare microsurgical skills between the two groups. RESULTS: There were no significant differences in the participants' baseline characteristics before microsurgical training between the groups with respect to age, sex, postgraduate year, surgical specialty, or mean GRS score (p < 0.05). There were also no significant differences in recipient sites between the two groups (p = 0.735). After training, the GRS scores in both groups were significantly improved (p = 0.000). However, in the actual microsurgical situations, the GRS scores were significantly higher in the experimental than control group (p < 0.05). There was no significant difference in the operative duration between the two groups (p < 0.13). CONCLUSION: Compared with a traditional training program, this step-by-step microsurgical curriculum based on our clinical scenario simulator results in significant improvement in acquisition of microsurgical skills.

[The incidence and time distribution of early transient intraocular pressure elevation after penetrating canaloplasty].

Objective: To report the incidence and time distribution of early transient intraocular pressure (IOP) elevation after penetrating canaloplasty. Methods: Retrospective case series study. Data of patients treated by penetrating canaloplasty for glaucoma in the Eye Hospital of Wenzhou Medical University from June 2015 to March 2020 were collected. Early transient IOP elevation was defined as an increase of IOP to over 21 mmHg on the first week to the third month after surgery followed by a decrease to 21 mmHg or less within 3 months. Main outcome measures included IOP, quantity of medication use, the occurrence time and duration of IOP elevation. Generalized estimating equations were used for statistical analysis, and measurement data with non-normal distribution was represented as M (Q1, Q3). Results: A total of 277 patients (315 eyes) achieved 360-degree catheterization of the canal successfully, and 299 eyes (94.9%) completed the postoperative 6-month follow-up. Thirty-four eyes (10.8%) had persistently high IOP, so the surgical treatment failed in them. Consequently, 234 patients (265 eyes) were enrolled in the analyses, including 161 males (184 eyes) and 73 females (81 eyes). The median age was 42 (26, 54) years, the mean preoperative IOP was (37.7±11.1) mmHg, and the mean number of drugs used was 3 (2, 4). The incidence of early transient IOP elevation was 43.0% (114/265) in all enrolled eyes, 42.7% (35/82) in eyes with primary open angle glaucoma, 37.8% (17/45) in eyes with primary angle closure glaucoma, 27.7% (13/47) in eyes with congenital glaucoma and 53.8% (49/91) in eyes with secondary glaucoma. The IOP began to increase on the first to fourth week in 91.2% (104/114) of eyes with early transient IOP elevation and reached the peak [21.3 mmHg to 54.8 mmHg; mean, (32.4±8.2) mmHg] in 88.6% (101/114) on the first to fifth week after surgery. The IOP elevation lasted for no more than 4 weeks in 69.3% (79/114) of eyes. Conclusions: Over 40.0% of patients with penetrating canaloplasty may experience postoperative transient IOP elevation. The incidence is relatively high in secondary glaucoma but low in congenital glaucoma. Most of the elevations and peak IOP occur within 1-4 weeks after surgery.

[Phacoemulsification combined with goniosynechialysis under a gonioscope in the treatment of angle-closure glaucoma: the effect of reopening the synechial anterior chamber angle].

A total of 170 consecutive patients (181 eyes) who were diagnosed with primary angle-closure glaucoma (PACG) and underwent phacoemulsification and intraocular lens implantation (PEI) combined with goniosynechialysis (GSL) with an instrument under a gonioscope in the Eye Hospital, Wenzhou Medical University from January 1, 2017 to December 31, 2019 were observed. Anterior chamber angle synechiae of 0 (0, 2) clock hour were released after PEI, while after combined goniosynechialysis, synechiae of 6 (3, 8) clock hours were further released. No matter in chronic PACG and acute PACG with cornea edema, the extent of anterior chamber angle synechiae was different before surgery and after PEI, and so was it in post-PEI and PEI-GSL prospectively (all P<0.01). Phacoemulsification alone can reopen the synechial anterior chamber angle in both chronic PACG and acute PACG in part, but not sufficiently. Combined goniosynechialysis under a gonioscope with an instrument is essential and effective.

Bone mineral density and trabecular bone score in elderly type 2 diabetes Southeast Asian patients with severe osteoporotic hip fractures.

INTRODUCTION: Studies show trabecular bone score (TBS) may provide information regarding bone quality independent of bone mineral density (BMD) in type 2 diabetes (DM2) patients. We analyzed our Southeast Asian severe osteoporotic hip fracture patients to study these differences. METHODS: We conducted a retrospective cross-sectional analysis of subjects admitted to Changi General Hospital, Singapore with severe osteoporotic hip fractures from 2014-2017 who had BMD performed. Electronic records were reviewed and subjects were classified as having diabetes according to the WHO 2019 criteria. DM2 patients were classified according to their HbA1c into well controlled (HbA1c < 7%) and poorly controlled (HbA1c ≥ 7%) DM2. RESULTS: Elderly patients with hip fractures present with average femur neck T scores at the osteoporotic range, however those with DM2 had higher BMD and TBS values compared to non DM2 patients. These differences were statistically significant in elderly women-poorly controlled elderly DM2 women with hip fracture had the highest total hip T-score (-2.57 ± 0.86) vs (-2.76 ± 0.96) in well controlled DM2 and (-3.09 ± 1.01) in non DM2 women with hip fracture, p < 0.001. In contrast, TBS scores were lower in poorly controlled DM2 women with hip fracture compared to well controlled DM2 women with hip fracture (1.22 ± 0.11) vs (1.24 ± 0.09), but these were still significantly higher compared to non DM2 women with hip fracture (1.19 ± 0.10), p < 0.001. In elderly men with hip fractures, univariate analysis showed no statistically significant differences in TBS or hip or LS BMD between those with poorly controlled DM2, well controlled DM2 and non DM2. The differences in TBS and BMD remained significant in all DM2 women with hip fractures even after adjustments for potential confounders. Differences in TBS and BMD in poorly controlled DM2 men with hip fractures only became significant after accounting for potential confounders. However, upon inclusion of LS BMD into the multivariate model these differences were attenuated and remained significant only between elderly women with well controlled DM2 and non DM2 women with hip fractures. CONCLUSIONS: Elderly patients with DM2 and severe osteoporosis present with hip fractures at a higher BMD and TBS values compared to non DM2 patients. These differences were significant after adjustment for confounders in all DM2 women and poorly controlled DM2 men with hip fractures, TBS differences were attenuated with the inclusion LS BMD. Further studies are needed to ascertain differences in BMD and TBS in older Southeast Asian DM2 patients with variable glycemic control and severe osteoporosis.

[Preliminary efficacy of penetrating canaloplasty in primary angle-closure glaucoma].

Objective: To evaluate the preliminary efficacy and safety of penetrating canaloplasty for treating primary angle-closure glaucoma (PACG). Methods: It is a prospective interventional case series study. Twenty-two patients (24 eyes) with PACG were treated with penetrating canaloplasty (video attached) at the Eye Hospital of Wenzhou Medical University from June 2015 to August 2018. This modified canaloplasty was performed by making a window at the corneal-scleral bed. Aqueous was redirected to the opening of Schlemm's canal after the canaloplasty with intension sutures. Postoperative follow-up was made at 1 day, 7 days, 1 month, 3 months, and 6 months. Surgical success was defined as intraocular pressure (IOP) ≤ 21 mmHg (1 mmHg=0.133 kPa) with glaucoma medication (quantified success) and without any glaucoma medication (complete success). Main outcome measures included IOP, number of medication, surgical success rate, complications, and filtering bleb status. One-way repeated measure ANOVA and rank sum test were used in statistical analysis. Results: Due to the failure of circumferential catheterization of the canal, 4 eyes converted to trabeculectomy. A total of 19 PACG patients (20 eyes) achieved the successful 360-degree catheterization of the canal, including 11 males and 8 females. The mean age was (54±7) years old (range: 41-65 years old), and the mean angle-closure range was (326.3±46.6) degrees. The mean preoperative IOP was (38.0±11.9) mmHg with the median medication number of 3 (range: 2-5). The mean postoperative IOP was (14.5±11.1), (16.1±6.0), (17.7±5.5), (15.7±5.0), and (15.4±3.7) mmHg at 1 day, 7 days, 1 month, 3 months, and 6 months, respectively. There was significant difference in IOP between postoperative and preoperative (all P<0.01). The median medication number (range) was 0 (0-3), 0 (0-2), 0(0-3), 0(0-2), and 0 (0-2) at the 5 time points, respectively. There was significant difference in medication number between postoperative and preoperative (all P<0.01). The quantified success rate was 95%(19/20), and the complete success rate was 90%(18/20) at 6 months. Postoperative complications were observed in 7 eyes (35%) of 20 PACG eyes, including 3 eyes (15%) with hyphema, 2 eyes (10%) with shallow anterior chamber, 1 eye (5%) with Descemet membrane detachment, and 1 eye (5%) with filtration obstruction at the trabeculum ostium. According to the results of slit lamp and ultrasound biomicroscopy examinations, 70% of the eyes (14/20) had no filtering bleb. Eight eyes (40%) with IOP spike were observed. Conclusion: Preliminary study shows penetrating canaloplasty is safe and effective in the treatment of PACG, but needs a longer follow-up. (Chin J Ophthalmol, 2019, 55: 448-453).

Validation of the PROMIS Sleep Disturbance and Sleep-Related Impairment item banks in Dutch adolescents.

PURPOSE: Sleep problems are common in adolescents and have a negative impact on daytime functioning. However, there is a lack of well-validated adolescent sleep questionnaires. The Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance and Sleep-Related Impairment item banks are well-validated instruments developed for and tested in adults. The aim of this study was to evaluate their structural validity in adolescents. METHODS: Test and retest data were collected for the Dutch-Flemish V1.0 PROMIS Sleep Disturbance (27) and Sleep-Related Impairment (16 items) item banks from 1046 adolescents (11-19 years). Cross-validation methods, Confirmatory (CFA), and Exploratory Factor Analyses (EFA) were used. Fit indices and factor loadings were used to improve the models. The final models were assessed for model fit using retest data. RESULTS: The one-factor Sleep Disturbance (CFI = 0.795, TLI = 0.778, RMSEA = 0.117) and Sleep-Related Impairment (CFI = 0.897, TLI = 0.882, RMSEA = 0.156) models could not be replicated in adolescents. Cross-validation resulted in a final Sleep Disturbance model of 23 and a Sleep-Related Impairment model of 11 items. Retest data CFA showed adequate fit for the Sleep-Related Impairment-11 (CFI = 0.981, TLI = 0.976, RMSEA = 0.116). The Sleep Disturbance-23 model fit indices stayed below the recommended values (CFI = 0.895, TLI = 0.885, RMSEA = 0.105). CONCLUSIONS: While the PROMIS Sleep Disturbance-23 for adolescents and PROMIS Sleep-Related Impairment-11 for adolescents provide a framework to assess adolescent sleep, additional research is needed to replicate these findings in a larger and more diverse sample.

Content validity of the Patient-Reported Outcomes Measurement Information System Sleep Disturbance and Sleep Related Impairment item banks in adolescents.

BACKGROUND: Sleep problems are common in adolescents and can have a negative impact on daily functioning and quality of life; therefore recognition of sleep problems is important. The PROMIS (Patient-Reported Outcomes Information System) Sleep Disturbance (SD) and Sleep Related Impairment (SRI) items banks are internationally used, well-validated instruments developed for and tested in adults. This study evaluates the content validity of the self- and proxy versions of the PROMIS-SD and the PROMIS-SRI in adolescents. METHODS: Experts (n = 6), adolescents (n = 24, 12-18 years) and their parents (n = 7) commented on the relevance and comprehensibility of the item banks. RESULTS: Experts considered all items relevant, only a few items were found irrelevant by adolescents and parents. The majority of items were comprehensible. The ability of parents to report on their adolescent's sleep was limited. CONCLUSION: The PROMIS-SD and PROMIS-SRI have adequate content validity in adolescents. Considering their psychometric robustness and the possibility of Computerized Adaptive Testing, which is efficient as well as patient-friendly, these item banks could prove very useful in the evaluation of adolescent sleep. The validity of the proxy scales, however, is limited considering the difficulties reported by the parents. Further psychometric evaluation of these scales in adolescents is required.

A case of catastrophic antiphospholipid syndrome: first report with advanced cardiac imaging using MRI.

This present case pertains to a 48-year-old woman with a history of antiphospholipid syndrome, who presented with progressive fatigue, generalized weakness, and orthopnea acutely. She had a prior diagnosis of antiphospholipid syndrome with recurrent deep vein thromboses (DVTs) and repeated demonstration of lupus anticoagulants. She presented in cardiogenic shock with markedly elevated troponin and global myocardial dysfunction on echocardiography, and cardiac catheterization revealed minimal disease. Cardiac magnetic resonance imaging was performed, which revealed findings of perfusion defects and microvascular obstruction, consistent with the pathophysiology of catastrophic antiphospholipid syndrome (CAPS). Diagnosis was made based on supportive imaging, including head magnetic resonance imaging (MRI) revealing multifocal, acute strokes; microvascular thrombosis in the dermis; and subacute renal infarctions. The patient was anticoagulated with intravenous unfractionated heparin and received high-dose methylprednisolone, plasmapheresis, intravenous immunoglobulin, and one dose each of rituximab and cyclophosphamide. She convalesced with eventual myocardial recovery after a complicated course. The diagnosis of CAPS relies on the presence of (1) antiphospholipid antibodies and (2) involvement of multiple organs in a microangiopathic thrombotic process with a close temporal association. The myocardium is frequently affected, and heart failure, either as the presenting symptom or cause of death, is common. Despite echocardiographic evidence of myocardial dysfunction in such patients, MRIs of CAPS have not previously been reported. This case highlights the utility in assessing the involvement of the myocardium by the microangiopathic process with MRI. Because the diagnosis of CAPS requires involvement in multiple organ systems, cardiac MRI is likely an underused tool that not only reaffirms the pathophysiology of CAPS, but could also clue clinicians in to the possibility of a diffuse thrombotic process.

Healthcare infrastructure and emotional support are predictors of CD4 cell counts and quality of life indices of patients on antiretroviral treatment in Free State Province, South Africa.

While many AIDS patients in sub-Saharan Africa are receiving antiretroviral treatment (ART) via public clinics, improvements in health status also depend on socioeconomic and psychological factors and quality of healthcare services. Inter-dependence between patients' clinical markers and quality of life indicators should be analyzed using comprehensive models. This longitudinal study compiled socioeconomic and clinical variables at six monthly intervals on patients receiving ART in South Africa; patients' ratings of quality of services and staff in "Assessment" and "Treatment" sites were assessed. Dynamic random effects models were estimated by maximum likelihood for CD4 cell counts and for quality of life indices (EQ-5D and Visual Analogue Scale), incorporating the inter-dependence between plasma HIV RNA levels and CD4 cell counts. The results showed that emotional support received by patients was a significant predictor (P<0.05) of CD4 cell counts and quality of life indices. Ratings of services and staff in Assessment and Treatment sites were significantly associated with CD4 cell counts and quality of life indices; CD4 cell count was a significant predictor of quality of life indices. The results indicated that it is important to compile socioeconomic and psychological variables for AIDS patients and monitor healthcare services for improving their health status and quality of life.

Isolated perforation of a duodenal diverticulum following blunt abdominal trauma.

Only 10% of duodenal diverticula are symptomatic. We present the case of a man who fell from a height of 6 ft, landing on his abdomen and presenting 4 h later with severe back pain and a rigid abdomen. At laparotomy, a perforated retroperitoneal duodenal diverticulum was found and repaired with an omental patch. No other injury was noted. Not only is this perforation unusual, but the absence of other injuries sustained during this minor blunt trauma makes this case unique. This case highlights the need for a high index of suspicion when managing patients with back or abdominal pain following minor trauma.

Highly active antiretroviral treatment and health related quality of life in South African adults with human immunodeficiency virus infection: A cross-sectional analytical study.

BACKGROUND: Health Related Quality of Life (HRQoL) is an important outcome in times of Highly Active Antiretroviral Treatment (HAART). We compared the HRQoL of HIV positive patients receiving HAART with those awaiting treatment in public sector facilities in the Free State province in South Africa. METHODS: A stratified random sample of 371 patients receiving or awaiting HAART were interviewed and the EuroQol-profile, EuroQol-index and Visual Analogue Scale (VAS) were compared. Independent associations between these outcomes and HAART, socio-demographic, clinical and health service variables were estimated using linear and ordinal logistic regression, adjusted for intra-clinic clustering of outcomes. RESULTS: Patients receiving HAART reported better HRQoL for 3 of the 5 EuroQol-dimensions, for the VAS score and for the EuroQol index in bivariable analysis. They had a higher mean EuroQol index (0.11 difference, 95% confidence interval [CI] 0.04; 0.23), and were more likely to have a higher index (odds ratio 1.9, 95% CI 1.1; 1.3), compared to those awaiting HAART, in multivariate analysis. Higher mean VAS scores were reported for patients who were receiving HAART (6.5 difference, 95% CI 1.3; 11.7), were employed (9.1, 95% CI 4.3; 13.7) or were female (4.7, 95% CI 0.79; 8.5). CONCLUSION: HAART was associated with improved HRQoL in patients enrolled in a public sector treatment program in South Africa. Our finding that the EuroQol instrument was sensitive to HAART supports its use in future evaluation of HIV/AIDS care in South Africa. Longitudinal studies are needed to evaluate changes in individuals' HRQoL.

HIV/AIDS, poverty and risky sexual behaviour in South Africa.

This paper employs data from the 1998 South African Demographic and Health Survey in exploring the nature of socio-economic inequalities in and determinants of risky sexual behaviour. Risky sexual behaviour was associated with poverty only in the case of multiple partnerships. Affluent women that have engaged in risky sexual behaviour were shown to be more likely to have cited negative perceptions about condom use as main reason for not using a condom at last sex. Poor women in turn were more likely to cite lack of knowledge about condoms and abstinence from condom use as main reason. Poverty plays little part in explaining differences in risky sexual behaviour, although higher education in some cases was associated positively with risky sexual behaviour. Risky sexual behaviour was associated with differences in age, urban residence and marital status. Coloured, Asian and White women were less likely than African women to have engaged in risky sexual behaviour. Violence and coercion were also associated with risky sexual behaviour. Women in affluent households that had engaged in risky sexual behaviour were more likely to have been mistreated by a husband or partner compared to poor women. There is no evidence of a definitive one-way causal relationship between poverty, gender and sexual behaviour and further research is required to elucidate this complex relationship.

The methodology of HIV/AIDS impact studies: a review of current practices.

This review of studies on the socio-economic impact of HIV/AIDS shows that diversity in methodological design, which often is a result of practical considerations and resource constraints rather than of poor design, is the norm. This limits the comparability of research findings. More detailed reporting on method, which is not the norm, can go some way towards facilitating such comparison. Furthermore, the review underlines the importance of exploring intervention issues in more detail. Researchers need to employ results in answering specific policy questions. Scope remains for more impact studies to be conducted in developing countries in general and in certain high prevalence countries in specific, i.e. Southern Africa. Studies that explore the urban/rural dynamics of and clients' perceptions and behavior in seeking care and support are necessary to better understand the epidemic. The role of community-based organizations, non-governmental organizations and other stakeholders in studies of this nature can be expanded. Larger studies generally have more statistical power, but smaller, in-depth studies can be equally valuable. A careful stratification of sample populations can enhance the quality of cross-sectional studies. Qualitative methods should be used to complement the current reliance on survey-based methods of data collection. More longitudinal studies are required to explore the long-term impacts of HIV/AIDS. HIV/AIDS training for fieldworkers should be standard in studies of this nature, while cognizance should be taken of the dangers of employing local people as fieldworkers in studies of such sensitive nature. Scope remains for the further empirical analysis of data from impact studies, which requires these data sets being made accessible to more researchers. In the longer term, an attempt at standardizing core modules in impact studies can help to improve our understanding of the impact of HIV/AIDS in different settings.

Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease.

Despite extensive deposition of putatively neurotoxic amyloid-beta (Abeta) protein in the brain, it has not been possible to demonstrate an association of Abeta deposits with neuronal loss in Alzheimer's disease (AD), and neuronal loss is minimal in transgenic mouse models of AD. Using triple immunostaining confocal microscopy and analyzing the images with the cross-correlation density map method from statistical physics, we directly compared Abeta deposition, Abeta morphology, and neuronal architecture. We found dramatic, focal neuronal toxicity associated primarily with thioflavin S-positive fibrillar Abeta deposits in both AD and PSAPP mice. These results, along with computer simulations, suggest that Abeta develops neurotoxic properties in vivo when it adopts a fibrillar beta-pleated sheet conformation.

Poverty, risky sexual behaviour, and vulnerability to HIV infection: evidence from South Africa.

This paper explores the relationship among poverty, risky sexual behaviour, and vulnerability to HIV infection, using data from the 1998 South African Demographic and Health Survey. Asset index was employed as proxy of socioeconomic status. Inequalities in health were measured using concentration index. Women in poorer households were slightly less knowledgeable about HIV/AIDS, while the socioeconomic inequalities in risky sexual behaviour were negligible. These small health gradients may reflect the limitations of population-based surveys in collection of information on sexual behaviour. The results may also mean that women in general are equally at risk of HIV infection, which means that more work is required to establish how factors other than knowledge on HIV/ AIDS and socioeconomic status stand to enhance the vulnerability of women to HIV/AIDS.

Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruption.

Neurites that pass through amyloid-beta deposits in Alzheimer disease (AD) undergo 3 changes: they develop phosphorylated tau immunoreactivity; the density of SMI-32-positive dendrites diminishes; and they also develop a marked alteration in their geometric features, changing from being nearly straight to being quite curvy. The extent to which the latter 2 phenomena are related to phosphorylated tau is unknown. We have now examined whether amyloid-beta deposits in APP695Sw transgenic mice, which have only rare phosphorylated tau containing neurites. develop these changes. We found that dendritic density is diminished within the boundaries of amyloid-beta plaques, with the greatest loss (about 80%, p < 0.001) within the boundaries of thioflavine S cores. Remaining dendrites within plaques develop substantial morphological alterations quantitatively similar to those seen in AD. A statistically significant but smaller degree of change in geometry was seen in the immediate vicinity around plaques, suggesting a propagation of cytoskeletal disruption from the center of the plaque outward. We examined the possible physiological consequences of this change in dendritic geometry using a standard cable-theory model. We found a predicted delay of several milliseconds in about one quarter of the dendrites passing through a thioflavine S plaque. These results are consistent with previous observations in AD, and suggest that thioflavine S-positive amyloid-beta deposits have a marked effect on dendritic microarchitecture in the cortex, even in the relative absence of phosphorylated tau alterations.

Interactions of conformationally biased north and south 2'-fluoro-2', 3'-dideoxynucleoside 5'-triphosphates with the active site of HIV-1 reverse transcriptase.

Molecular dynamics simulations of a ternary complex of HIV-1 reverse transcriptase (RT), double-stranded DNA, and bound dideoxynucleoside-5'-triphosphate (RT-DNA-ddNTP), utilizing the ddNTPs ddATP, betaFddATP, and alphaFddATP, explain the experimentally observed order of potency of these 5'-triphosphates as inhibitors of RT: ddATP > betaFddATP > alphaFddATP. On the basis of RT's known preference to bind the incoming dNTP (or ddNTP) with a north conformation at the polymerase site, alphaFddATP, which in solution prefers almost exclusively a north conformation, was predicted to be the most potent inhibitor. However, Tyr115, which appears to function as a steric gate to preclude the binding of ribonucleoside 5'-triphosphates, prevents the effective binding of alphaFddATP in its preferred north conformation. The south-biased betaFddATP, while able to bind to RT without hindrance by Tyr115, has to pay a high energy penalty to be flipped to the active north conformation at the polymerase site. Finally, the more flexible and less conformationally biased ddATP is able to switch to a north conformation at the RT site with a smaller energy penalty than betaFddATP. These results highlight the opposite conformational preferences of HIV-1 RT for alphaFddATP and betaFddATP and help establish conformational guidelines for optimal binding at the polymerase site of this enzyme.

Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias.

The cortex of the brain is organized into clear horizontal layers, laminae, which subserve much of the connectional anatomy of the brain. We hypothesize that there is also a vertical anatomical organization that might subserve local interactions of neuronal functional units, in accord with longstanding electrophysiological observations. We develop and apply a general quantitative method, inspired by analogous methods in condensed matter physics, to examine the anatomical organization of the cortex in human brain. We find, in addition to obvious laminae, anatomical evidence for tightly packed microcolumnar ensembles containing approximately 11 neurons, with a periodicity of about 80 microm. We examine the structural integrity of this new architectural feature in two common dementing illnesses, Alzheimer disease and dementia with Lewy bodies. In Alzheimer disease, there is a dramatic, nearly complete loss of microcolumnar ensemble organization. The relative degree of loss of microcolumnar ensembles is directly proportional to the number of neurofibrillary tangles, but not related to the amount of amyloid-beta deposition. In dementia with Lewy bodies, a similar disruption of microcolumnar ensemble architecture occurs despite minimal neuronal loss. These observations show that quantitative analysis of complex cortical architecture can be applied to analyze the anatomical basis of brain disorders.