Risk of severe COVID-19 in patients with inflammatory rheumatic diseases treated with immunosuppressive therapy in Scotland.

OBJECTIVE: To investigate the association of severe coronavirus disease 2019 (COVID-19) in patients with inflammatory rheumatic diseases (IRDs) treated with immunosuppressive drugs. METHOD: A list of 4633 patients on targeted - biological or targeted synthetic - DMARDs in March 2020 was linked to a case-control study that includes all cases of COVID-19 in Scotland. RESULTS: By 22 November 2021, 433 of the 4633 patients treated with targeted DMARDS had been diagnosed with COVID-19, of whom 58 had been hospitalized. With all those in the population not on DMARDs as the reference category, the rate ratio for hospitalized COVID-19 associated with DMARD treatment was 2.14 [95% confidence interval (CI) 2.02-2.26] in those on conventional synthetic (cs) DMARDs, 2.01 (95% CI 1.38-2.91) in those on tumour necrosis factor (TNF) inhibitors as the only targeted agent, and 3.83 (95% CI 2.65-5.56) in those on other targeted DMARDs. Among those on csDMARDs, rate ratios for hospitalized COVID-19 were lowest at 1.66 (95% CI 1.51-1.82) in those on methotrexate and highest at 5.4 (95% CI 4.4-6.7) in those on glucocorticoids at an average dose > 10 mg/day prednisolone equivalent. CONCLUSION: The risk of hospitalized COVID-19 is elevated in IRD patients treated with immunosuppressive drugs compared with the general population. Of these drugs, methotrexate, hydroxychloroquine, and TNF inhibitors carry the lowest risk. The highest risk is associated with prednisolone. A larger study is needed to estimate reliably the risks associated with each class of targeted DMARD.

Incident ischaemic stroke and Type 2 diabetes: trends in incidence and case fatality in Scotland 2004-2013.

AIM: To describe trends in first ischaemic stroke incidence and case fatality in adults with and without a diagnosis of Type 2 diabetes prior to their ischaemic stroke event in Scotland between 2004 and 2013. METHODS: Using population-wide hospital admission, death and diabetes datasets, we conducted a retrospective cohort study. Negative binomial and logistic regression models were used to calculate year-specific incidence and case-fatality rates for people with Type 2 diabetes and for people without diabetes. RESULTS: During 41.0 million person-years of follow-up there were 69 757 ischaemic stroke events. Type 2 diabetes prevalence among patients who experienced ischaemic stroke increased from 13.5% to 20.3% between 2004 and 2013. Stroke incidence rates declined by 2.7% (95% CI 2.4, 3.0) annually for people with and without diabetes [diabetes/year interaction: rate ratio 0.99 (95% CI 0.98, 1.01)]. Type 2 diabetes was associated with an increased risk of ischaemic stroke in men [rate ratio 1.23 (95% CI 1.17, 1.30)] and women [rate ratio 1.41 (95% CI 1.35, 1.48)]. Case-fatality rates were 14.2% and 12.7% in people with Type 2 diabetes and without diabetes, respectively. Case fatality declined by 3.5% (95% CI 2.7, 4.5) annually [diabetes/year interaction: odds ratio 1.01 (95% CI 0.98, 1.02)]. CONCLUSIONS: Ischaemic stroke incidence declined no faster in people with a diagnosis of Type 2 diabetes than in people without diabetes. Increasing prevalence of Type 2 diabetes among stroke patients may mean that declines in case fatality over time will be less marked in the future.

Preliminary investigation of Brain Network Activation (BNA) and its clinical utility in sport-related concussion.

BACKGROUND: The clinical diagnosis and management of patients with sport-related concussion is largely dependent on subjectively reported symptoms, clinical examinations, cognitive, balance, vestibular and oculomotor testing. Consequently, there is an unmet need for objective assessment tools that can identify the injury from a physiological perspective and add an important layer of information to the clinician's decision-making process. OBJECTIVE: The goal of the study was to evaluate the clinical utility of the EEG-based tool named Brain Network Activation (BNA) as a longitudinal assessment method of brain function in the management of young athletes with concussion. METHODS: Athletes with concussion (n = 86) and age-matched controls (n = 81) were evaluated at four time points with symptom questionnaires and BNA. BNA scores were calculated by comparing functional networks to a previously defined normative reference brain network model to the same cognitive task. RESULTS: Subjects above 16 years of age exhibited a significant decrease in BNA scores immediately following injury, as well as notable changes in functional network activity, relative to the controls. Three representative case studies of the tested population are discussed in detail, to demonstrate the clinical utility of BNA. CONCLUSION: The data support the utility of BNA to augment clinical examinations, symptoms and additional tests by providing an effective method for evaluating objective electrophysiological changes associated with sport-related concussions.

Lysophosphatidic acid mediates fibrosis in injured joints by regulating collagen type I biosynthesis.

OBJECTIVE: Articular cartilage is a highly specialized tissue which forms the surfaces in synovial joints. Full-thickness cartilage defects caused by trauma or microfracture surgery heal via the formation of fibrotic tissue characterized by a high content of collagen I (COL I) and subsequent poor mechanical properties. The goal of this study is to investigate the molecular mechanisms underlying fibrosis after joint injury. DESIGN: Rat knee joint models were used to mimic cartilage defects after acute injury. Immunohistochemistry was performed to detect proteins related to fibrosis. Human fetal chondrocytes and bone marrow stromal cells (BMSCs) were used to study the influence of the lipid lysophosphatidic acid (LPA) on COL I synthesis. Quantitative PCR, ELISA and immunohistochemistry were performed to evaluate the production of COL I. Chemical inhibitors were used to block LPA signaling both in vitro and in vivo. RESULTS: After full-thickness cartilage injury in rat knee joints, stromal cells migrating to the injury expressed high levels of the LPA-producing enzyme autotaxin (ATX); intact articular cartilage in rat and humans expressed negligible levels of ATX despite expressing the LPA receptors LPAR1 and LPAR2. LPA-induced increases in COL I production by chondrocytes and BMSCs were mediated by the MAP kinase and PI3 Kinase signaling pathways. Inhibition of the ATX/LPA axis significantly reduced COL I-enriched fibrocartilage synthesis in full-thickness cartilage defects in rats in favor of the collagen II-enriched normal state. CONCLUSION: Taken together, these results identify an attractive target for intervention in reducing the progression of post-traumatic fibrosis and osteoarthritis.

Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation.

BACKGROUND: Targeting both mitochondrial bioenergetics and glycolysis pathway is an effective way to inhibit proliferation of tumour cells, including those that are resistant to conventional chemotherapeutics. METHODS: In this study, using the Seahorse 96-well Extracellular Flux Analyzer, we mapped the two intrinsic cellular bioenergetic parameters, oxygen consumption rate and proton production rate in six different pancreatic cancer cell lines and determined their differential sensitivity to mitochondrial and glycolytic inhibitors. RESULTS: There exists a very close relationship among intracellular bioenergetic parameters, depletion of ATP and anti-proliferative effects (inhibition of colony-forming ability) in pancreatic cancer cells derived from different genetic backgrounds treated with the glycolytic inhibitor, 2-deoxyglucose (2-DG). The most glycolytic pancreatic cancer cell line was exquisitely sensitive to 2-DG, whereas the least glycolytic pancreatic cancer cell was resistant to 2-DG. However, when combined with metformin, inhibitor of mitochondrial respiration and activator of AMP-activated protein kinase, 2-DG synergistically enhanced ATP depletion and inhibited cell proliferation even in poorly glycolytic, 2-DG-resistant pancreatic cancer cell line. Furthermore, treatment with conventional chemotherapeutic drugs (e.g., gemcitabine and doxorubicin) or COX-2 inhibitor, celecoxib, sensitised the cells to 2-DG treatment. CONCLUSIONS: Detailed profiling of cellular bioenergetics can provide new insight into the design of therapeutic strategies for inhibiting pancreatic cancer cell metabolism and proliferation.

Association of epidural analgesia in labor with neurodevelopmental outcomes in premature infants born at <29 weeks of gestational age.

OBJECTIVE: To explore associations between epidural administration to mothers in labor with neurodevelopmental outcomes at 3 years corrected age in preterm infants born <29 weeks gestational age. STUDY DESIGN: Infants born <29 weeks gestational age between 2006 and 2012 were included. Our primary outcome was a composite of death or neurodevelopmental impairment at 3 years corrected age. Infants were divided into those whose mothers did or did not receive epidural analgesia in labor. Univariable and multivariable regression was used for analysis. RESULTS: There were 548 infants in the no epidural analgesia group and 121 in the epidural analgesia group. The adjusted odds ratio (95%CI) of neurodevelopmental impairment or death in the epidural group was 1.25 (0.82-1.93). Propensity score-matched results were 1.32 (0.79-2.22). CONCLUSION: Preterm infants born <29 weeks gestational age to mothers who received epidural analgesia during labor were not associated with poor neurodevelopmental outcomes at 3 years corrected age.

Effects of H(2)O(2) exposure on human sperm motility parameters, reactive oxygen species levels and nitric oxide levels.

Research has revealed that reactive oxygen species (ROS) negatively affect sperm function, both in vivo and in vitro. Sperm preparation techniques for assisted reproductive technologies (ART) are potential causes for additional ROS production. This study aimed to correlate the concentration of exogenous H(2)O(2) with sperm motility parameters and intracellular ROS and nitric oxide (NO) levels to reiterate the importance of minimising ROS levels in ART. Human spermatozoa from 10 donors were incubated and exposed to different exogenous H(2)O(2) concentrations (0, 2.5, 7.5 and 15 mum). Subsequently, motility was determined using computer-aided semen analysis, while ROS (2,7-dichlorofluorescin diacetate) and NO (diaminofluorescein-2/diacetate) were analysed using fluorescence-activated cell sorting. Results showed that H(2)O(2) did affect the sperm parameters. Exogenous H(2)O(2) was detrimental to motility and resulted in a significant increase in overall ROS and NO levels. A significant increase in static cells was seen as well. It is important to elucidate the mechanisms between intracellular ROS levels with sperm motility parameters. While this experiment demonstrated a need to reduce exogenous ROS levels during ART, it did not illustrate the cause and effect relationship of intracellular ROS and NO levels with sperm motility. Further research needs to be conducted to define a pathological level of ROS.

Computed tomographic emphysema distribution: relationship to clinical features in a cohort of smokers.

Computed tomography (CT) scanning allows precise assessment of both the extent and distribution of emphysema. There has been little work on the relationship between the distribution of emphysema and clinical features of the disease. The current study investigated the association between clinical features and distribution of emphysema. A total of 129 patients with smoking-related chronic obstructive pulmonary disease underwent CT assessment of the extent and distribution of their emphysema (core/rind and upper/lower zone predominance). Emphysema was found predominantly in the upper/core zone and this distribution was related to the extent of disease. Core predominance was associated with lower forced expiratory volume in one second (FEV(1)), FEV(1)/forced vital capacity ratio and body mass index (BMI); and with higher BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) index and Medical Research Council dyspnoea score. Upper-zone predominance was associated with female sex and an increased total St George's Respiratory Questionnaire score. Using multiple linear regression age, sex and whole lung emphysema severity were independently associated with core/rind distribution, while sex and whole lung emphysema severity were independently related to upper/lower distribution. Distribution of emphysema related best to clinical features when divided into core/rind predominance. However, the effects were not independent of the extent of emphysema. Increased age and female sex were related to disease distribution independent of emphysema severity. These findings may be related to differences in development of emphysema.

Physiological fluctuation of (99m)Tc-sestamibi uptake in normal mammary glands: a systematic investigation in female rats.

BACKGROUND: Scintimammography is an imaging tool for the diagnosis and management of primary breast tumors. There remains a significant knowledge gap regarding the physiological fluctuations in the basal level of (99m)Tc-sestamibi uptake in normal mammary tissues with respect to the female reproductive cycle. PURPOSE: To systematically characterize (99m)Tc-sestamibi uptake in normal mammary tissues in female Sprague Dawley (SD) rats in different estrous phases. MATERIAL AND METHODS: The exact phase of the reproductive cycle was determined in 18 female SD rats. Each rat was sacrificed at 20 min after (99m)Tc-sestamibi injection (14.8 MBq/kg). The mammary glands were dissected, and the radioactivity uptake was measured by gamma counting. RESULTS: Tc-99m-sestamibi uptake oscillates by about twofold and reaches a maximum at the proestrous phase of the rat reproductive cycle. CONCLUSION: Tc-99m-sestamibi uptake fluctuates significantly in normal mammary tissues in synchrony with the female reproductive cycle, and peaks in the proestrous phase in rats, which is equivalent to the early to mid-follicular phase in the human menstrual cycle. This finding will likely benefit the detection of breast lesions that may otherwise be obscured by fluctuating background signals in surrounding normal breast tissues.

Why should clinicians understand epidemiology?

This article summarises the importance of epidemiology to clinicians and aims to show how an understanding of epidemiological concepts can make an important contribution to optimum clinical practice in its broadest sense. Epidemiological principles can be applied to clinical practice in interpreting the results of diagnostic tests, assessing and communicating risk and prognosis, and in identifying appropriate treatment for individual patients. They are also of value to clinicians involved in planning, monitoring and improving services, teaching medical students and postgraduates, critically appraising medical literature, and undertaking or supervising research.

Characterization of SH-SY5Y human neuroblastoma cell growth over glass and SU-8 substrates.

The physical properties of substrates can have profound effects on the structure and function of cultured cells. In this study, we aimed to examine the viability, adherence, and morphological and functional variations between SH-SY5Y human neuroblastoma cells cultured on SU-8 surfaces compared with control surfaces composed of borosilicate glass, which are routinely used for cell culture. The SU-8 polymer has been extensively studied for its biocompatibility, but there has been little investigation into the characteristic differences between cells cultured on SU-8 when compared with glass. SH-SY5Y cells were cultured within polydimethylsiloxane wells on both SU-8 and glass substrates for up to 72 h after which flow cytometry and enzyme-linked immunosorbent assay analysis was performed to examine cell viability and neurotoxicity. Immunocytochemistry was also performed to analyze the morphological and functional characteristics of the cells. Atomic force microscopy was performed to measure surface roughness and to map cell-substrate interactions. Nanoindentation testing was used to characterize the mechanical properties of polymer surface. Results showed that SH-SY5Y cells grown on SU-8 have significantly improved viability and increased morphological and functional characteristics of neurodevelopment. The results from this study suggest that the mechanical properties of the polymer are optimal for the study of cultured cell lines, which could account for the increased viability, adherence, and morphological and functional characteristics of neurodevelopment. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2129-2138, 2017.

The effects of short-term stimulation on fibroblast spreading in an in vitro 3D system.

Although the short-term effects of mechanical and biochemical stimulation on cell protein and DNA production have recently begun to be evaluated using 3D models, the effects that such stimulation have on cell morphology and adaptation remains unclear. Using a custom-built bioreactor, we were able to create a systematic model to examine the short-term effects of stimulation on cell morphology in a 3D model, specifically by evaluating cell spreading as the short-term indicator of cell adaptation. Fibroblasts were seeded on a porous poly(L-lactic acid) scaffold and cultured in a computerized bioreactor for 24 h under various uniaxial strains (0, 0.6, 3, 6%) and frequencies (0.0125, 0.125 Hz). Also, the effects of transforming growth factor (TGF-beta1) (1, 10, 100 ng/mL) were examined on static, nonstimulated cells-scaffold constructs after 24 h. Fibroblasts that had been subjected to mechanical stretching were found to exhibit significantly more spreading than the static control group. Conversely, TGF-beta1 between 1 and 100 ng/mL did not produce any significant difference in fibroblast spreading from the control groups after 24 h. Collectively, the findings suggest that cell morphology and adaptation may be affected by short-term mechanical stimulation, as seen by increased cell spreading by the fibroblasts under these experimental conditions.

Patient characteristics associated with risk of first hospital admission and readmission for acute exacerbation of chronic obstructive pulmonary disease (COPD) following primary care COPD diagnosis: a cohort study using linked electronic patient records.

OBJECTIVES: To investigate patient characteristics of an unselected primary care population associated with risk of first hospital admission and readmission for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). DESIGN: Retrospective open cohort using pseudonymised electronic primary care data linked to secondary care data. SETTING: Primary care; Lothian (population approximately 800,000), Scotland. PARTICIPANTS: Data from 7002 patients from 72 general practices with a COPD diagnosis date between 2000 and 2008 recorded in their primary care record. Patients were followed up until 2010, death or they left a participating practice. MAIN OUTCOME MEASURES: First and subsequent admissions for AECOPD (International Classification of Diseases (ICD) 10 codes J44.0, J44.1 in any diagnostic position) after COPD diagnosis in primary care. RESULTS: 1756 (25%) patients had at least 1 AECOPD admission; 794 (11%) had at least 1 readmission and the risk of readmission increased with each admission. Older age at diagnosis, more severe COPD, low body mass index (BMI), current smoking, increasing deprivation, COPD admissions and interventions for COPD prior to diagnosis in primary care, and comorbidities were associated with higher risk of first AECOPD admission in an adjusted Cox proportional hazards regression model. More severe COPD and COPD admission prior to primary care diagnosis were associated with increased risk of AECOPD readmission in an adjusted Prentice-Williams-Peterson model. High BMI was associated with a lower risk of first AECOPD admission and readmission. CONCLUSIONS: Several patient characteristics were associated with first AECOPD admission in a primary care cohort of people with COPD but fewer were associated with readmission. Prompt diagnosis in primary care may reduce the risk of AECOPD admission and readmission. The study highlights the important role of primary care in preventing or delaying a first AECOPD admission.

Acepromazine. Effects on intraocular pressure.

We investigated the effects of the topical application of acepromazine maleate on the intraocular pressure (IOP) in 27 adult rhesus monkeys. The monkeys were divided into two groups: group 1 (16 monkeys) had both eyes normal, and group 2 (11 monkeys) had experimental chronic glaucoma in one eye and a normal fellow eye. One drop of 1% acepromazine maleate solution was instilled in one eye of monkeys in group 1 and in the glaucomatous eye of monkeys in group 2; the other eye served as the control. The IOP was measured before drug administration and 1, 4, 8, 24, and 32 hours after, with detailed slit-lamp examination of the anterior segment. Acepromazine produced no change in IOP in eyes in group 1, but it produced a fall in pressure in all eyes with high IOP in group 2, evident 1 hour after instillation, maximal between 4 and 8 hours, and still remaining after 32 hours. The pupil showed no change in size, but a transient ptosis was observed in the treated eye in all monkeys.

Metabolic and biochemical status of articular cartilage following cryopreservation and transplantation: a rabbit model.

To determine the fate of transplanted cryopreserved articular cartilage, an animal model employing the proximal humerus in the rabbit has been developed. Previous studies have been hindered by problems of postoperative joint instability, secondary injury due to immobilization, and paucity of cartilage for analysis. This experiment demonstrates the survival and function of transplanted cartilage by quantitative assessment of metabolic and biochemical parameters. Forty-five New Zealand white rabbits underwent transplantation of the right proximal humerus. In 29 animals, the proximal half of the humerus was resected and replaced by a cryopreserved osteoarticular allograft. Autograft procedures were carried out in the remaining animals. Following sacrifice at 3, 6, 9, and 12 months postoperatively, articular cartilage was analyzed for gross appearance, collagen synthesis, proteoglycan synthesis, and water, hydroxyproline, hexosamine, and hexuronic acid contents. The results indicate that the cryopreserved osteoarticular allografts retained their metabolic and biochemical integrity and behaved as viable and biologically functional units 1 year postoperatively.

Cryopreserved articular chondrocytes grow in culture, maintain cartilage phenotype, and synthesize matrix components.

For osteochondral allograft transplantation to be successful, chondrocytes must survive preservation and retain their capacity to produce normal matrix components: proteoglycans and Type II collagen. Clinical success with osteochondral allograft transplantation has created an increased demand for supplies of suitable cartilage-bearing grafts. This demand has stimulated attempts to find successful methods for low temperature storage of cartilage for "banking" and heightened interest in cartilage cryobiology. In order to achieve the maximum viability of cryopreserved articular cartilage, previous comprehensive studies have focused on rates and temperatures of freezing, cryoprotective agents, and methods and influences of thawing. This study presents evidence that cryopreserved articular chondrocytes maintain their ability to grow in tissue culture following thawing and to produce normal matrix components. Chondrocytes isolated from Japanese white rabbits were divided into groups of fresh controls and experimental cryopreserved cells. Cells were incubated in dimethylsulfoxide, frozen at a rate of -1 degrees C/min, stored at -79 degrees C, rapidly thawed, and plated for culture. Growth rates were comparable in all groups. In all groups, typical chondroid characteristics were maintained throughout 14 days of culture. Typical cartilage phenotypic characteristics included maintenance of polygonal and rhomboidal cells, cell aggregation, proteoglycan production, and Type II collagen synthesis. This investigation strongly indicates that articular chondrocyte cryopreservation yields viable, functional cells and although these results cannot be directly extrapolated to intact adult articular cartilage, they do give further support for low temperature banking of cartilage-bearing allografts for transplantation.

The effect of cryopreservation on the biomechanical behavior of bovine articular cartilage.

The short-term effect of cryopreservation on specific mechanical behaviors of bovine articular cartilage has been investigated. A flat-ended nonporous indentor was used in a nondestructive, repetitive, axisymmetric unconstrained testing system. Cyclical indentation from a fixed position to a fixed load was applied until a steady-state load-deformation relationship (limit cycle) was achieved. Indentation behaviors measured from the limit cycles of each articular cartilage specimen before and after treatment were compared. Testing was done in vitro using fresh, mature bovine radiocarpal joints. Twenty pairs of cartilage-subchondral bone cores from anatomically similar sites on contralateral joints were separated into three groups; thickness controls, dimethylsulfoxide (DMSO) controls, and cryopreserved experimental samples. Thickness controls and DMSO controls were used to examine the isolated effects of the thickness measurement and DMSO incubation techniques on articular cartilage indentation characteristics. Experimental samples were cryopreserved using DMSO, their thicknesses similarly measured and indentation behaviors examined. Following testing, histological and histochemical assessment of the specimens confirmed the nondestructive nature of the tests. Intra- and intergroup comparisons of controls and experimentals revealed no statistical differences in the mechanical behaviors measured from the limit cycle or in cartilage thickness. These results indicate that the cryopreservation protocol used did not have an effect that we could measure on these specific mechanical behaviors of articular cartilage.

Gait pattern in the early recovery period after stroke.

The gait patterns of eighteen patients who had had a single infarct due to obstruction of the middle cerebral artery were evaluated within one week after the patients had resumed independent walking and before a gait rehabilitation program had been initiated. Gait was analyzed with use of motion analysis, force-plate recordings, and dynamic surface electromyographic studies of the muscles of the lower extremities. The patterns of motion of the lower extremity on the hemiplegic side had a stronger association with the clinical severity of muscle weakness than with the degree of spasticity, balance control, or phasic muscle activity. There was a delay in the initiation of flexion of the hip during the pre-swing phase, and flexion of the hip and knee as well as dorsiflexion of the ankle progressed only slightly during the swing phase. During the stance phase, there was decreased extension of the hip that was related to decreased muscle effort and a coupling between flexion of the knee and dorsiflexion of the ankle. The abnormal patterns of motion altered the velocity, the length of the stride, the cadence, and all phases of the gait cycle. The duration of the pre-swing phase was prolonged for the patients who had the slowest gait velocities. There also were abnormal movements of the upper extremity, the trunk, the pelvis, and the lower extremity on the unaffected side in an effort to compensate for the decreased velocity on the hemiplegic side. As velocity improved, these abnormal movements decreased. Therefore, the goal of therapy should be to improve muscle strength and coordination on the hemiplegic side, especially during the pre-swing phase.

The effects of tibial rotation on posterior translation in knees in which the posterior cruciate ligament has been cut.

BACKGROUND: One of the most useful clinical tests for diagnosing an isolated injury of the posterior cruciate ligament is the posterior drawer maneuver performed with the knee in 90 degrees of flexion. Previously, it was thought that internally rotating the tibia during posterior drawer testing would decrease posterior laxity in a knee with an isolated posterior cruciate ligament injury. In this study, we evaluated the effects of internal and external tibial rotation on posterior laxity with the knee held in varying degrees of flexion after the posterior cruciate and meniscofemoral ligaments had been cut. MATERIALS AND METHODS: Twenty cadaveric knees were used. Each knee was mounted in a fixture with six degrees of freedom, and anterior and posterior forces of 150 N were applied. The testing was conducted with the knee in 90 degrees, 60 degrees, 30 degrees, and 0 degrees of flexion with the tibia in neutral, internal, and external rotation. All knees were tested with the posterior cruciate and meniscofemoral ligaments intact and transected. Repeated-measures analysis of variance was used for statistical analysis. RESULTS: At 30 degrees, 60 degrees, and 90 degrees of flexion, there was a significant increase in posterior laxity following transection of the posterior cruciate and meniscofemoral ligaments. At 60 degrees and 90 degrees of flexion, there was significantly less posterior laxity when the tibia was held in internal compared with external rotation. At 0 degrees and 30 degrees of flexion, there was no significant difference in posterior laxity when the tibia was held in internal compared with external rotation. CONCLUSIONS: After the posterior cruciate and meniscofemoral ligaments had been cut, posterior laxity was significantly decreased by both internal and external rotation of the tibia. Internal tibial rotation resulted in significantly less laxity than external tibial rotation did at 60 degrees and 90 degrees of knee flexion.

Microfabricated microneedles: a novel approach to transdermal drug delivery.

Although modern biotechnology has produced extremely sophisticated and potent drugs, many of these compounds cannot be effectively delivered using current drug delivery techniques (e.g., pills and injections). Transdermal delivery is an attractive alternative, but it is limited by the extremely low permeability of skin. Because the primary barrier to transport is located in the upper 10-15 micron of skin and nerves are found only in deeper tissue, we used a reactive ion etching microfabrication technique to make arrays of microneedles long enough to cross the permeability barrier but not so long that they stimulate nerves, thereby potentially causing no pain. These microneedle arrays could be easily inserted into skin without breaking and were shown to increase permeability of human skin in vitro to a model drug, calcein, by up to 4 orders of magnitude. Limited tests on human subjects indicated that microneedles were reported as painless. This paper describes the first published study on the use of microfabricated microneedles to enhance drug delivery across skin.