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Edentulism with associated severe bone loss is a widespread condition that hinders the use of common dental implants. An additively manufactured subperiosteal jaw implant (AMSJI) was designed as an alternative solution for edentulous patients with Cawood and Howell class V-VIII bone atrophy. A biomechanical evaluation of this AMSJI for the maxilla in a Cawood and Howell class V patient was performed via finite-element analysis. Occlusal and bruxism forces were incorporated to assess the loading conditions in the mouth during daily activities. The results revealed a safe performance of the implant structure during the foreseen implantation period of 15 years when exerting average occlusion forces of 200 N. For the deteriorated state of class VIII bone atrophy, increased stresses on the AMSJI were evaluated, which predicted implant fatigue. In addition, excessive bruxism and maximal occlusion forces might induce implant failure due to fatigue. The models predicted bone ingrowth at the implant scaffolds, resulting in extra stability and secondary fixation. For all considered loading conditions, the maximal stresses were located at the AMSJI arms. This area is most sensitive to bending forces and, hence, allows for further design optimization. Finally, the implant is considered safe for normal daily occlusion activities., (Copyright © 2021 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: An accurate classification of patients with brain metastases (BMs) is an important foundation to guide individualised treatment decisions and to formulate BM cohorts for modern clinical trials., Methods: Six thousand and thirty-one patients with newly diagnosed BM from different solid tumours treated between 1986 and 2020 were identified from the Vienna Brain Metastasis Registry., Results: A rising fraction of patients presented with asymptomatic BM during the observation period (1986-1999: 20.2% vs 2010-2020: 30.6%; p < 0.001). Especially, oncogene-addicted non-small-cell lung cancer (NSCLC) and BRAF (v-Raf murine sarcoma viral oncogene homolog)-positive melanoma had a higher rate of asymptomatic BM presentation compared with wild-type tumours (p < 0.05). Significant changes of initial BM treatment approaches were observed with a decrease of neurosurgical procedures (1986-1999: 30.8% vs 2010-2020: 19.5%) and an increase of radiation treatments (1986-1999: 65.0% vs 2010-2020: 73.3%) and systemic therapies (1986-1999: 1.0% vs 2010-2020: 2.0%; p < 0.001). Median overall survival (OS) was heterogeneous between primary tumour entities but with an overall increase over the decades (median OS 1986-1999: 5 months vs 2010-2020: 7 months; p = 0.001). Survival times were longer in patients with oncogene-addicted NSCLC, BRAF-positive melanoma and hormone receptor-positive breast cancer compared with the other cancer subtypes (p > 0.05)., Conclusion: Our data highlight shifting trends in the symptomatic presentation and in treatment strategies of patients with BM over the last decades. Entity specific aspects and, in particular, the presence of targetable driver mutation impact the clinical presentation and prognosis. Future BM specific trials need to address the modern composition of BM cohorts and the distinct clinical course of patients with targetable driver mutations., Competing Interests: Conflict of interest statement ASB has research support from Daiichi Sankyo (≤10,000€), Roche (>10,000€) and honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo (all <5000€) as well as travel support from Roche, Amgen and AbbVie. GW received restricted travel grants from NX Development Corp. MP has received research support from Böhringer-INgelheim, GlaxoSmithKline, Merck Sharp & Dome and Roche and honoraria for lectures, consultation or advisory board participation from Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Merck Sharp & Dome. AMS has received travel support from PharmaMar. All other authors report no conflict of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A double-twist torsion testing technique has been developed using a 316 stainless steel as an exemplar material to experimentally assess recrystallization behavior and determine the non-recrystallization temperature (T nr ). This new method was compared to the traditional methods of double-hit compression and multi-step hot torsion testing. The double-twist torsion test allows T nr to be related to the extent of austenite recrystallization through measurements of fractional softening while accommodating multiple deformation and recrystallization steps with a single specimen. The double-twist torsion test resulted in average T nr values similar to those determined with multi-step hot torsion, and a partially recrystallized microstructure was observed in the vicinity of the calculated T nr for all three methods. The ability of the double-twist torsion test to relate the experimental T nr to the evolution of austenite recrystallization via fractional softening measurements while incorporating effects of multiple deformation steps offers an advantage over traditional methods for quantifying changes in austenite recrystallization during thermomechanical processing.

A new approach for non-isothermal tempering analysis utilizing dilatometry is proposed and was carried out on a medium carbon steel with high silicon and additions of Mo and V for secondary hardening. The method includes a second non-isothermal step performed with the same heating rate (2 °C/min) used for the first step in order to create a baseline for analysis. The results were correlated with several other characterization techniques. Mössbauer spectroscopy confirmed the formation of transition carbides by auto-tempering as well as the presence of retained austenite decomposition (stage II) and cementite precipitation (stage III), which demonstrated significant overlap. Electrical resistivity measurements were correlated with dislocation densities obtained through X-ray diffraction analysis. Transmission electron microscopy dark field images confirmed the secondary hardening assessment from dilatometry.

The ecology of mosquito vectors and malaria parasites affect the incidence, seasonal transmission and geographical range of malaria. Most malaria models to date assume constant or linear responses of mosquito and parasite life-history traits to temperature, predicting optimal transmission at 31 °C. These models are at odds with field observations of transmission dating back nearly a century. We build a model with more realistic ecological assumptions about the thermal physiology of insects. Our model, which includes empirically derived nonlinear thermal responses, predicts optimal malaria transmission at 25 °C (6 °C lower than previous models). Moreover, the model predicts that transmission decreases dramatically at temperatures > 28 °C, altering predictions about how climate change will affect malaria. A large data set on malaria transmission risk in Africa validates both the 25 °C optimum and the decline above 28 °C. Using these more accurate nonlinear thermal-response models will aid in understanding the effects of current and future temperature regimes on disease transmission., (© 2012 Blackwell Publishing Ltd/CNRS.)

Background: With the rollout of antiretroviral therapy in South Africa and its potential to prolong the lives of HIV-infected individuals, understanding the sexual behavior of HIV-positive people is essential to curbing secondary HIV transmission., Methods: We surveyed 3,819 HIV-positive patients during their first visit to an urban wellness clinic and a rural wellness clinic., Results: Urban residents were more likely than rural residents to have current regular sex partners (75.1% vs. 46.0%; chi2 odds ratio [OR] = 3.531; P < 0.001), to have any current sexual partners (75.3% vs. 51.2%; chi2 OR = 2.908; P < 0.001), and to report consistent condom use with regular partners (78.4% vs. 48.3%; chi2 OR = 3.886; P < 0.001) and with casual partners (68.6% vs. 48.3%; chi2 OR = 2.337; P < 0.001). In multivariate analysis, independent predictors of consistent condom use with regular partners included across gender, urban residence, and higher education levels; for women, disclosure and younger age; and for men only, no history of alcohol consumption. Male and female participants with a casual sexual partner were less likely to use a condom consistently with regular partners. Additionally, urban residence and a CD4 count greater than 200 cells/mm as well as (for women only) a higher household income and a history of alcohol consumption were predictors of having a regular sexual partner., Conclusions: HIV prevention programs in South Africa that emphasize the importance of condom use and disclosure and are tailored to the needs of their attending populations are critical given the potential for HIV-infected individuals to resume risky sexual behavior with improving health.

The purpose of this study was to evaluate the ability of the Accordion Pill (AP), a novel controlled release gastroretentive unfolding dosage form (DF), to increase the bioavailability of riboflavin (RF) in humans. Three formulations containing 75 mg of RF and differing in release rate (immediate release (IR) capsule, AP#1, and AP#2) were administered with a low-calorie meal. Gastric residence time (GRT) of the AP was assessed by magnetic resonance imaging. Serial blood and urine samples were taken and assayed for RF. The AP demonstrated prolonged (up to 10.5 h) GRT in humans. Significant elevation in RF bioavailability (209+/-37%, mean+/-S.E.) was achieved by the AP#1 in comparison to the IR capsule. A correlation was established between the in-vitro release rates from DF and bioavailability of RF in humans, and it was modeled taking into account the saturable nature of RF absorption transport and its narrow absorption window (NAW) in the upper gastro-intestinal tract. It is anticipated that the AP will provide a valuable pharmaceutical solution to enhance therapy with NAW drugs.

Urate and ascorbate play a major role in the defense mechanism of the brain against oxidative damage induced by traumatic brain injury. The severity and extent of brain damage are known to increase with age. This may be due to different basal levels of endogenous antioxidants, and/or to impaired ability of the old brain to recruit and elevate the levels of antioxidants following injury. To investigate this hypothesis, we measured basal ascorbate and urate levels in the hippocampus, using microdialysis in young, adults and old rats, and performed closed head injury (CHI) in young (5-6 weeks) and old rats (19-20 months). Basal ascorbate, but not urate levels in old rats were significantly lower than in the adults. The ability of the old rats to increase ascorbate levels after CHI was significantly lower than that of the young ones, as indicated by lower levels of ascorbate and urate in the dialysate of old rats. This lower level of antioxidant mobilization in the old brain may explain the extended damage found in histology. Evaluation of hippocampal cell loss (p<0.05) and axonal degeneration in the corpus callosum showed more extensive damage in old as compared to young rats (chi(2)=4.25; p<0.05). These findings shed more light on the susceptibility of old rat brain to CHI-induced oxidative damage.

This study compares non-absorbable, ethyl cellulose (EC) membranes and absorbable, chitosan (CH) membranes in a rabbit model. Bone regeneration, evaluated by radiological and pathological parameters, was seen in both groups. In the EC group the process was faster but was followed by a sharp decrease, whereas in the CH group it was slower and continuous.

Reactive oxygen species (ROS) are a major cause of secondary brain injury following head trauma. Low molecular weight antioxidants (LMWA) protect the tissue against oxidative damage caused by ROS. In the present study, we measured the extracellular levels of the LMWA ascorbic acid and uric acid in the rat brain before, during and after experimental closed head injury (CHI). A dialysis probe was inserted into the right ventral hippocampus through a chronically implanted guide. CHI was applied to the left hemisphere using a weight-drop device. CHI induced a rapid but transient increase in ascorbic acid levels. Uric acid levels increased to 250% of baseline shortly after CHI and remained elevated at 2 h after CHI. Previous results show that the overall reducing power of brain tissue decreases following CHI. Together with previous results, the current findings suggest that ascorbic acid and uric acid are mobilized from brain cells to the extracellular space.

Procarboxypeptidase U (proCPU) is the plasma precursor of carboxypeptidase U (CPU, carboxypeptidase R. plasma carboxypeptidase B or activated thrombin-activatable fibrinolysis inhibitor, TAFIa). CPU removes C-terminal lysine residues that act as plasminogen binding sites from partially degraded fibrin, thereby down-regulating plasminogen activation and fibrinolysis. The present study was carried out as a pilot study to examine whether the plasma proCPU concentration is related to the presence of coronary artery disease (CAD) and/or to levels of established risk indicators for CAD, in a case-control study of 110 men requiring coronary artery bypass grafting (CABG) because of stable angina pectoris. The preoperative plasma proCPU level in the CABG patients was significantly higher than in population-based controls (1029 +/- 154 vs. 974 +/- 140 U/L, p <0.05). In addition, in a subset of the patients (n = 31 ) the proCPU concentration, which was significantly lower on the third postoperative day (-17 +/- 10%), had increased significantly on the sixth day (+14 +/- 12%) after surgery, compared with the preoperative level. In both patients and controls, proCPU concentration was strongly and positively associated with factor VII amidolytic activity and protein C activity, suggesting a common mechanism modulating the plasma levels of these proteins. Otherwise, statistically significant correlations with proCPU were group-specific. In the patients, proCPU correlated significantly with plasma fibrinogen and protein S. In the controls, proCPU correlated significantly with concentrations of cholesterol in plasma. VLDL and LDL. In addition, proCPU correlated significantly with C-reactive protein and haptoglobin levels in the controls only, indicating that also inflammatory mechanisms are involved in the regulation of plasma proCPU. These results suggest that a mechanism exists by which fibrinolytic function is impaired in a manner that is likely to result in more stable fibrin deposits and increase the risk of precocious CAD as well as early occlusion of venous bypass grafts.

Vein graft failure remains a major problem after coronary artery bypass grafting. Occlusion in the first weeks usually is caused by thrombosis, whereas intimal hyperplasia and eventually atherosclerotic changes with superimposed thrombus formation underlie subsequent closure. The present investigation was conducted as a pilot study to examine whether perturbations of haemostatic function predispose to early saphenous vein graft occlusion after coronary artery bypass grafting. Pre- and postoperative determinations (performed on the first, third, and sixth postoperative days) of haemostatic factors and inhibitors were related to the presence of graft occlusion assessed by angiography at 3 months after surgery in 100 men undergoing elective coronary artery bypass grafting for stable angina pectoris. Occlusion of one or more vein grafts within three months of surgery occurred in 23 of the 100 patients examined. The percentage increase in plasma plasminogen activator inhibitor-1 activity on the first postoperative day was significantly higher in patients who subsequently were found to have vein graft occlusion (p<0.05). Otherwise no postoperative haemostatic measurements were found to predict early vein graft closure. A perturbed plasma plasminogen activator inhibitor-1 response to coronary artery bypass grafting tentatively could be added to the vessel-specific factors that remain the main determinants of early vein graft closure.

Multiple glomus tumors are extremely rare and differ from the more common solitary glomus tumors in their clinical presentation and histological features. The authors report a case of multiple glomus tumors of the right hand in a 65-year-old man, its treatment, and a review of the features of this uncommon tumor. The tumor usually presents as a painful, firm, purplish, solitary nodule of the extremities, especially in the nail bed. Multiple glomus tumors are described as softer, more compressible, bluish nodules and they occur with less frequency than solitary tumors. They are often inherited in an autosomal dominant pattern. The authors present a case of multiple glomus tumors of the right hand, in which many small, painful, red papules were grouped in the right hypothenar region. The patient was treated by wide excision of the lesion and coverage of the defect with an ulnar artery forearm flap.

The expanding indications for coronary artery bypass graft (CABG) and cardiac valves replacement have caused an increase in the number of sternal infections. The common treatment includes appropriate antibiotics, early debridement, and transposition of muscle flaps with or without skin grafts. When other treatments have proved unsatisfactory, we have used the great omentum for wound closure. During the last five years, 16 patients (10 women, six men, median age 63 years) underwent repair of infected sternotomy wounds by the transposition of the great omentum, after failure of pectoralis major or rectus abdominis muscle flaps (n = 9). Seven patients underwent transposition of the great omentum as the first choice. The omentum covers the sternal defect well and the closure was reliable.

In the present study, the regulation of acetylcholine release from the ventral hippocampus by gamma-aminobutyric acid (GABA) was investigated in vivo. GABA receptor agonists and antagonists were administered locally in the medial septum and the adjacent vertical limb of the diagonal band of Broca, or in the hippocampus by retrograde dialysis. Acetylcholine release was measured in the ventral hippocampus. In addition, the modulation of acetylcholine release via septal benzodiazepine binding sites was assessed by intraseptal administration of an agonists and an antagonist at the benzodiazepine binding site. Intraseptal administration of the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen, but not the agonist of the benzodiazepine binding site midazolam, decreased acetylcholine release in the hippocampus. The GABA(A) receptor antagonist bicuculline and the antagonist of the benzodiazepine binding site flumazenil, but not the GABA(B) receptor antagonist 3-N-(3,4,-dichlorobenzyl) aminopropyl-P-diethoxymethyphosphinic acid (CGP 52432) increased acetylcholine release in the hippocampus upon intraseptal administration. The same GABA receptor ligands were administered in the ventral hippocampus. CGP 52432 induced a small increase in acetylcholine release, whereas baclofen, muscimol and bicuculline did not affect local acetylcholine release. Thus, endogenous GABA causes tonic inhibition of acetylcholine release in the ventral hippocampus via septal GABA(A) receptors and, to a lesser extent, via GABA(B) receptors in the medial septum and hippocampus. The GABAergic inhibition in the medial septum is reduced by antagonists of the benzodiazepine binding site.

BACKGROUND AND HYPOTHESIS: Dobutamine stress echocardiography is a well-established diagnostic method for investigating patients with suspected ischemic coronary disease. A positive test result is based on systolic parameters, but left ventricular filling parameters also are affected by myocardial ischemia. The aim of the present study was to study changes in both systolic and diastolic left ventricular variables throughout the test, including the period following it. METHODS AND RESULTS: Seven healthy control subjects (group I), 10 patients with chest pain but without significant coronary stenosis (group II), and 17 patients with significant coronary stenosis (group III) were entered in the study. Dobutamine stress echocardiography was performed according to a preset standardized protocol. Two-dimensional echocardiography and transmitral pulsed-Doppler images were stored for later analysis at rest, low dose, peak dose, and 5 minutes after termination of the dobutamine infusion. The wall motion score index increased from rest to low dose by 6.7% +/- 6.4% (P < 0.05) and to the peak dose by 39.1% +/- 9.9% (P < 0.001) in all three groups. The increase from rest to peak dose was significantly higher in groups I and II than in group III (P < 0.01). There was a significant increase in the atrial velocity-time integral (A-VTI) at peak dose in groups I and II (64.8% +/- 52.1% and 103.8% +/- 68.7%, respectively; P < 0.05 and <0.001), but no change in group III was noted. At the peak dose, A-VTI was significantly greater in groups I and II than in group III (P < 0.05). Among the 17 patients with proved coronary stenosis, 15 (88.2%) had a positive systolic response and 14 (82.3%) had a positive diastolic response, expressed as an A-VTI increase of

The factor V (Arg506-->Gln) mutation confers an increased risk of deep vein thrombosis, whereas its role in saphenous vein graft closure after coronary artery bypass grafting (CABG) remains unclear. This study examined the anticoagulant response to activated protein C (APC ratio) in relation to the surgical trauma and the significance of the factor V Leiden mutation in determining postoperative thrombin generation and fibrin formation and the risk of early vein graft occlusion. A total of 108 men undergoing elective CABG for exertional angina pectoris (mean age 61.1 +/- 8.7 years) were examined. The patency of saphenous vein grafts was studied at routine reangiography three months after CABG. Of 100 patients who underwent reangiography, 23 had one or more occluded vein grafts at reangiography. Heterozygosity for the factor V (Arg506-->Gln) mutation tended to be associated with early saphenous vein graft occlusion (5/11 carriers vs. 18/89 non-carriers with graft occlusion, chi2 = 3.52, p = 0.06), whereas pre- and postoperative APC ratios did not. Pre- and postoperative determinations of prothrombin fragment 1+2, thrombin-antithrombin complexes and soluble fibrin levels did not differ between patients with and without the mutation. Early saphenous vein graft occlusion after CABG could tentatively be added to deep vein thrombosis as a vascular complication that can be attributed to the factor V (Arg506-->Gln) mutation.

In the present study, the role of medial septal receptors in behaviour-induced increase in acetylcholine (ACh) release in hippocampus was investigated using dual-probe microdialysis in combination with a simple behavioural procedure. gamma-Aminobutyric acid (GABA) and glutamate receptor agonists and antagonists were administered by retrograde dialysis into the medial septal area, while ACh was measured in the ventral hippocampus. Rats were behaviourally activated by immobilization or handling, but only handling was performed during drug-treatment. The GABAA receptor agonist muscimol did not affect ACh release, but blocked the handling-induced increase in ACh release completely. In addition, muscimol administration induced behavioural activity. Administration of the GABAA receptor antagonist bicuculline increased ACh release more than 2-fold. However, handling-induced increase in ACh release, expressed as percentage of drug-induced release, was similar to that of controls. Administration of the glutamate receptor agonists N-methyl-D-aspartate (NMDA) and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the septal area increased hippocampal ACh levels, but reduced the handling-induced increase in ACh release. The NMDA antagonist, 3-((R)-2-carboxypiperazin-4-yl) (CPP) increased ACh levels moderately, and reduced handling-induced increase in ACh release. However, similarly to muscimol, CPP administration induced behavioural activity. The AMPA/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) did not affect behaviour or basal ACh levels, but attenuated the handling-evoked ACh release. We conclude that the handling-induced increase in hippocampal ACh levels is mediated via stimulation of septal non-NMDA, and possibly NMDA receptors, whereas GABAA receptors are probably not involved. The feasibility of the experimental design is further discussed.

The involvement of muscarinic autoreceptors in the regulation of hippocampal acetylcholine levels during acetylcholinesterase inhibition was examined by perfusing the acetylcholinesterase inhibitor neostigmine bromide (10, 100 or 1000 nM) alone and in the presence of the muscarinic receptor antagonist atropine methylnitrate (10 microM), in resting and behaviourally-activated animals. In resting animals, local perfusion of neostigmine caused a dose-dependent increase in acetylcholine levels. Coadministration of atropine did not affect basal levels in the presence of 10 nM neostigmine, but increased acetylcholine levels approximately four and 11-fold in the presence of 100 nM and 1000 nM neostigmine, respectively. In animals which were behaviourally activated by handling, acetylcholine levels increased two- to three-fold in the presence of all neostigmine concentrations. However, the handling-induced increase in acetylcholine levels was somewhat smaller with 1000 nM neostigmine as compared to 10 nM neostigmine. Atropine had no effect on handling-induced acetylcholine output in the presence of 10 nM neostigmine, but caused greater and longer increases in the presence of 100 nM and 1000 nM neostigmine. These data indicate that acetylcholine levels are greatly reduced by autoinhibition at higher levels of acetylcholine esterase inhibition. The handling-evoked increase in acetylcholine levels is only moderately affected by the level of acetylcholinesterase inhibition, despite the participation of autoreceptors in the handling effect at higher levels of acetylcholinesterase inhibition.

Skin surface proteolytic activity in the living animal was determined by a sensitive, non-invasive methodology developed in our laboratory. A non-leaky well was constructed on the shaved back of an anesthetized guinea pig. The well contained the reaction mixture including the substrate 125I-S-carboxymethylated insulin B-chain (ICMI). The proteolytic activity was shown to be time-dependent. The activity was strongly inhibited by pepstatin A, indicating the involvement of aspartic proteinase(s) such as cathepsin D and/or E. Pretreatment of the skin with propylene glycol blocked the proteolytic activity. The present study demonstrates the presence of proteolytic activity located on skin surface using a unique, non-invasive method for in situ proteinase determination in the living animal.

Current treatment of acute organophosphate (OP) poisoning includes a combined administration of a cholinesterase reactivator (oxime), a muscarinic receptor antagonist (atropine) and an anticonvulsant (diazepam). This treatment is not adequate since it does not prevent neuronal brain damage and incapacitation. Here, as in a recent review it is stated that other therapeutic approaches may improve protection. Former studies on the "direct effects" of oximes led to the conclusion that drug-induced inhibition of acetylcholine (ACh)-release shortly (1 min) after the acute OP-intoxication, could prevent and counteract convulsions and improve survival. In general, the accumulation of ACh in the synaptic cleft is considered to be responsible for the symptoms that ultimately lead to death. Therefore, prevention or suppression of this excessive accumulation of ACh could be a generic approach to antagonize OP-poisoning. Preliminary evidence for this concept has been put forward. Evaluation of drugs that would be able to prevent and counteract ACh accumulation, led to the conclusion that adenosine receptor agonists could be promising candidates. Pilot experiments demonstrated that intramuscular administration of the adenosine receptor agonists NECA (5'-N-ethylcarboxamido-adenosine) or CPA (N6-cyclopentyl adenosine) 1 min following a subcutaneous soman poisoning (1.5-2LD50) in rats, resulted in (1) prevention or postponement of chewing, salivation, convulsive activity, and respiratory distress (cholinergic symptoms), (2) improvement of survival rate (24 h), (3) a low level of extracellular brain ACh, as opposed to high levels of extracellular brain ACh in untreated animals. It is concluded that (1) adenosine agonists protect acutely soman-poisoned rats without the need of additional treatment with atropine, oxime or diazepam, (2) prevention of ACh accumulation in this way may be a new generic approach in the treatment of OP-poisoning.

The present study demonstrated a noninvasive procedure for in situ determination of stratum corneum aspartic proteinase in the living animal. A non-leaky well, containing [125I]S-carboxymethylated insulin B-chain (ICMI) as a substrate, was constructed on the shaved back of anesthetized guinea pigs and rats. The enzymatic activity was determined by measuring the radiolabeled trichloroacetic acid soluble material. We demonstrated pepstatin-sensitive proteinase activity bound to the skin surface indicating the involvement of aspartic proteinase(s) such as cathepsin D and/or E. Aged rats had about six fold lower activity than young animals. The proteinase activity was inhibited by the alkylating agent mechlorethamine and by the cosmetic propylene glycol. A similar procedure was carried out with intact human skin pieces obtained during plastic surgery. The activity was inhibited by antihuman cathepsin D antibodies. Cathepsin D was immunohistochemically localized in the corneal and granular layers of the epidermis. Skin surface aspartic proteinase/cathepsin D activity may serve as a marker for skin aging or for certain skin disorders leading to a new approach to their medical treatments.

By examining the effect of dopamine (DA) D3 receptor stimulation on locomotor activity and extracellular levels of DA in striatum we show that inhibition of locomotor activity induced by DA D3 receptor-selective agonists is mediated by two interacting mechanisms: (1) directly via the stimulation of DA D3 receptors that inhibit locomotor activity, and (2) indirectly via a decrease in extracellular levels of DA. Thus, the moderately DA D3 receptor-selective agonist R-(+)-7-OH- DPAT (R-(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetralin) decreased locomotor activity after administration of 10 nmol/kg and extracellular DA levels in accumbens and striatum after administration of 30 nmol/kg. A decrease in locomotor activity that coincided with a decrease in extracellular DA levels in striatum was observed after administration of 100 nmol/kg of the DA D3 receptor-selective agonist PD128907 ((+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3 b]-1,4-oxasin-9-ol. In combination with the partial, DA D3 receptor-selective agonist PD151328 (2-[4[3-(4-phenyl)-1- piperazinyl)propoxy]phenyl]-benzamidazole), a reversal of the attenuating effect of PD128907 on locomotor activity was observed, without an effect on extracellular levels of DA. In combination with a low--10 nmol/kg--dose of haloperidol, a reversal of the inhibitory effect of PD128907 on locomotor activity was observed that coincided with an increase in extracellular levels of DA. In the presence of 0.5 mg/kg amphetamine, PD128907 decreased amphetamine-induced locomotor activity. This effect could be reversed by PD151328.

In the present study, glutamate receptor agonists and antagonists were administered by retrograde microdialysis into either the medial septum/vertical limb of the diagonal band (MS/vDB), or hippocampus, and the output of acetylcholine (ACh) was measured in the hippocampus by using intracerebral microdialysis. Perfusion with N-methyl-D-aspartate (NMDA) and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the MS/vDB caused an incrase in ACh output in the hippocampus. This increase was completely blocked by coadministration of their respective antagonists D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Perfusion in the MS/vDB with kainic acid also caused an increase in ACh output, but coadministration of CNQX attenuated the increase only partially. Perfusion with D-AP5 and CNQX alone in the septal probe did not affect ACh output from the hippocampus. In contrast to the results of septal administration of NMDA and AMPA, local perfusion with the same drugs in the hippocampus caused a decrease in ACh output. Whereas the results of septal administration of drugs indicate that septal cholinergic neurons probably receive excitatory glutamatergic innervation, the decrease in ACh output caused by administration of NMDA and AMPA in the hippocampus is poorly understood.

A description is given of a new procedure to align series of tilted graphs, made with an electron microscope, for computer tomographic purposes. The procedure uses the coordinates of three projected markers to calculate parameters needed for the reconstruction. To that end the procedure computes the direction of the tilt-axis, the translation and rotation parameters, the tilt-angle of every micrograph, and the spatial coordinates of the individual markers with their centre of gravity as origin of the coordinate system. A searching technique, based on cross-correlation, is described to locate accurately the micrographs markers.

Forty-three women, in a series of 150, participated in a prospective study that examined their chest walls for deformities 3 months after maximal tissue expansion for single-breast reconstruction. Computed tomography imaging was used for this purpose. Twenty-one patients underwent immediate breast reconstruction and the other 22 patients underwent delayed reconstruction. Fifty-three percent had some chest wall abnormality. In the delayed group, chest wall deformities were more statistically significant (p < 0.001). Our findings suggest that chest wall deformity is a common occurrence after maximal tissue expansion for breast reconstruction.

The effects of local administration of cholinergic drugs on the release of acetylcholine in the septo-hippocampal system were investigated using intracerebral microdialysis. Dialysis probes were implanted in the cell-body area of septo-hippocampal neurones in the medial septal area, and in the terminal area of the same neurones in the ventral hippocampus. Drugs were administered locally via the dialysis probe. Administration of the mixed muscarinic/nicotinic receptor agonist carbachol caused a decrease, whereas administration of the muscarinic receptor antagonist methyl-atropine caused an increase in the output of acetylcholine in both the hippocampus and the medial septal area. In contrast, perfusion with the same drugs and the acetylcholine esterase inhibitor neostigmine bromide in the septal area had little or no effect on the output of acetylcholine in hippocampus. The results indicate that acetylcholine autoreceptors are localised on nerve terminals in medial septal area and hippocampus, and exert an inhibitory control over acetylcholine release. However, autoreceptors seem to be sparse or absent on dendrites and cell bodies of septo-hippocampal cholinergic neurones.

To assess the efficacy of the topical anesthetic cream, EMLA, in alleviating the pain produced by infiltration of local anesthetic prior to surgical skin biopsies, a randomized, double-blind, placebo-controlled study was performed on 54 patients undergoing 162 excisional biopsies. Both pain induced by needle insertion and pain induced by local injection were significantly diminished after topical application of EMLA cream. However, part of the effect was placebo, because the placebo ointment (Vaseline) also produced significant pain alleviation.

Using back projection for reconstruction and tilt series of Epon or Lowicryl embedded and sectioned material, we demonstrated: (1) a reduction in thickness of 50% for Epon and 80% for Lowicryl sections, and (2) a non-uniform density distribution along the electron-optical axis in sections. The highest density was found at the vacuum exposed side of the section. The formvar side of the section showed a similar increase in density, but not to the same extent. Minimalization of electron exposure, even without pre-exposure, did not affect the reconstructed thickness, nor did it affect the non-uniform density distribution. However, parallax measurements showed that at 150K, collapse of Epon sections does not take place. For EM-tomography of plastic embedded material our findings imply that at the top and bottom portion of the sections the dimensions of the reconstructed structures are distorted, but that in the middle portion the dimensions are reliably retained.

This article describes a rare malignant schwannoma invading the left mandible in a 42-year-old man. The clinical presentation, inconclusive radiographic findings, and light microscopic histology are included. The appropriate surgical treatment could be determined only intraoperatively when frozen sections provided the exact tumor margins. The patient subsequently received adjuvant treatment by brachytherapy.

Factor VII (FVII) coagulant activity has been proven to be associated with the risk of future fatal coronary heart disease (CHD) in middle-aged men. Recent studies have emphasized the role of triglyceride-rich lipoproteins and FVII genotype in determining plasma levels of FVII protein and activity. The present study was undertaken to examine whether FVII activity state and protein concentration in fasting plasma are altered in young men with proven myocardial infarction (MI) and examined the relations of FVII to subfractions of apo B-containing lipoproteins and the Arg-->Gln polymorphism in the FVII gene. Activated FVII (FVIIa) was determined by a clotting assay using soluble, recombinant, truncated tissue factor. A total of 94 men with a first MI before the age of 45 (mean age +/- SD, 39.6 +/- 4.5 years) were included in the study along with 99 population-based, age-matched control subjects. In addition to FVIIa and FVII antigen (FVII:Ag), a panel of FVII activity assays were included for comparison with previous work in this field. The plasma level of FVII:Ag was higher in patients than in control subjects when the entire groups were compared (537 +/- 128 versus 479 +/- 93 ng/mL, P < .001), the differences being accounted for by patients with hypertriglyceridemic lipoprotein phenotypes. In contrast, FVIIa was similar in patients and control subjects (4.6 +/- 1.4 versus 4.3 +/- 1.3 ng/mL, NS), which means that the proportion of FVIIa molecules was unaltered or even lower in the patients. As expected, the Arg-->Gln polymorphism significantly influenced both FVII mass and activity levels. In addition, presence of the Gln allele appeared to be associated with a lower proportion of fully active FVII molecules. The polymorphism also affected the relation between the plasma concentration of VLDL and FVII:Ag. The triglyceride content and particle number of all VLDL subfractions, irrespective of particle size, correlated fairly strongly with FVII mass determinations but not at all with FVIIa. HDL cholesterol concentration, on the other hand, presumably reflecting the efficiency of lipoprotein lipase-mediated lipolysis of VLDL, related significantly to the FVIIa level. The Arg-->Gln polymorphism, independent of lipoprotein effects, explained 5% to 10% of the variation in FVII mass and activity. In conclusion, the present findings speak against a role of FVII as a risk factor for CHD, because a significantly increased potential for activation of coagulation (ie, raised basal concentration of FVIIa) was not observed among young postinfarction patients.(ABSTRACT TRUNCATED AT 400 WORDS)

In the present study, the cardiac outflow of endothelin, noradrenaline and neuropeptide Y was investigated in 13 patients undergoing first time coronary angioplasty (PTCA) due to stenosis of the left anterior descending coronary artery. During PTCA there was an increase in the coronary sinus levels of endothelin but no detectable changes in neuropeptide Y or noradrenaline concentrations. It is therefore concluded that endothelial damage rather than myocardial ischaemia is the cause of endothelin release during PTCA.

This article describes the case of a patient who suffered an electrical full thickness burn of the chest wall and a concomitant osteomyelitic complication of two ribs. A review of the existing literature on bone and joint changes after burns is presented. Osteomyelitis of ribs must be kept in mind while treating patients for chest wall burns.

In 1,800 patients undergoing cardiac surgery over a 2-year period, 11 incidents of abnormal inlet pressure elevations occurred before the membrane oxygenators. In 3 patients, the oxygenators had to be changed during cardiopulmonary bypass. This complication was found to be caused by fibrin formation possibly secondary to precipitation of fibrinogen with other coagulation factors in the heat exchangers of the oxygenators during the cooling phase. Large amounts of fibrin were demonstrated in the heat exchanger of the oxygenators. After careful washing of the apparatus, plasmin was added and fibrin was detected by measuring D-dimer levels. In heat exchangers from uneventful operations, only trace amounts of fibrin were found. Because there were no cold agglutinins demonstrated in the patients before surgery, cryoprecipitation studies were performed soon after surgery. When the patients' plasma samples were studied at different temperatures, from 37 degrees C down to 3 degrees C, cryoprecipitates or a gel (in 1 patient only) were formed. This indicated that there might be something abnormal with regard to fibrinogen-fibrin formation. The study patients were therefore investigated after the acute phase of the operation had ended for various coagulation factors, as well as for fibrin gel network characteristics. The results were compared with those of a control group (n = 10) with uneventful operations. There were no differences between the groups with regard to levels of coagulation factors VII and VIII and von Willebrand factor, although they were increased in both groups. The mean levels of coagulation inhibitors, antithrombin and Protein S, were slightly lower in the study patients. All of these patients had a highly pathologic, ie, tight fibrin gel network, except for the patient in whose sample a gel formed, despite being treated with aspirin or oral anticoagulants. The network was also tighter in some of the controls (v middle-aged reference individuals), although it was significantly tighter in the patients. It is concluded that some individuals who have an increased tendency to form tighter fibrin gel networks might be at increased risk for a severe complication during cardiac surgery performed under hypothermia.

Graft closure remains a major problem after coronary artery bypass surgery. While a number of graft characteristics influencing the risk of occlusion have been defined, the role of haemostatic factors and inhibitors has not been studied in detail. The present study examined the time course of changes in blood coagulation and fibrinolytic function after coronary artery bypass grafting in 20 consecutive patients. Pre- and postoperative determinations of haemostatic factors and inhibitors were also related to the presence of graft occlusion assessed by angiography at three months after surgery. A broad panel of haemostatic tests was used preoperatively, on the first, third and eight postoperative days, and at three months after surgery. A particular emphasis was placed on fibrinogen, factor VII activity, von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) activity, anticoagulant proteins C and S, thrombin-antithrombin complex and D-dimer. A marked activation of the coagulation cascade was noted postoperatively along with enhanced degradation of cross-linked fibrin. The degree of activation of blood coagulation and fibrinolysis differed widely between individuals and appeared to relate only partly to the acute phase reaction produced by the surgical trauma. Preoperative values of haemostatic factors and inhibitors showed fairly weak associations with the levels of postoperative determinations.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study, the overflow of acetylcholine (ACh) in the septo-hippocampal system was studied using intracerebral microdialysis in freely moving rats. Dialysis probes were implanted in the ventral hippocampus and in the medial septal area (MS), including a part of the ventral limb of the diagonal band of Broca (VDB). Dialysis samples were analysed 'on-line' using HPLC with post column enzymatic conversion and electrochemical detection. Local perfusion of 1 mumol/l of the sodium-channel blocker tetrodotoxin (TTX) through the probe resulted in 94% and 92% decrease in extracellular levels of ACh in the hippocampus and the septal area, respectively. The effects of septal manipulation on the efflux of ACh in the hippocampus were studied by electrical stimulation of the septal area and by administering drugs via the septal probe. Electrical stimulation of the MS/VDB caused a 336% increase in the output of ACh in the hippocampus. Perfusion of 3 mumol/l TTX through the septal probe caused a maximal decrease of 56% in the output of ACh in the ventral hippocampus. When perfused in the MS/VDB, the excitatory amino-acid agonists N-methyl-D-aspartate (NMDA) (100 mumol/l) and kainic acid (10 mumol/l) caused an increase in the extracellular level of ACh in the hippocampus by 83% and 161%, respectively. Thus, the overflow of ACh in the hippocampus and the septal area both depend on neuronal impulse flow. The extracellular level of ACh in the hippocampus is at least partially dependent on impulse flow in septo-hippocampal fibres. Moreover, the output of ACh in the hippocampus can be manipulated by electrical and pharmacological stimulation of the MS/VDB.

Tissue factor pathway inhibitor (TFPI) activity was quantified in two cohorts of young male post-infarction patients and in population-based control subjects to explore the relationships between TFPI activity and plasma lipoproteins and to address the issue of coordinate regulation of factor VII and TFPI in hyperlipidaemia and premature coronary heart disease (CHD). Participants were investigated in the fasting state and after an oral fat load. Basal TFPI activity and factor VII antigen (VIIag) levels were found to be increased in the patients (TFPI activity 1.25 +/- 0.23 vs 1.17 +/- 0.20 U/ml, p < 0.05; VIIag 537.7 +/- 127.7 vs 479.4 +/- 93.4 ng/ml, p < 0.001). The parallel increase was accounted for by patients with hypertriglyceridaemic lipoprotein phenotypes. In contrast, the level of activated factor VII (VIIa) neither differed significantly between patients and controls, nor between patients with different lipoprotein phenotypes. The elevated TFPI activity in the patients was closely associated with the plasma level of dense low density lipoprotein (LDL) particles (r = 0.46, p < 0.001) and with the plasma concentration of the small, dense high density lipoprotein (HDL) subspecies HDL3b (r = 0.34, p < 0.01).

A low voltage (24 V) electrical deep burn of the hand injured a professor of applied physics when performing an experiment in his laboratory. The potential hazard of the equipment is described, the injuries are reported and the literature is reviewed.

Surgery has become progressively more reliant on technology. The technique of colonic anastomosis utilizing the biofragmentable anastomotic ring (BAR) is one such example. The benefits of therapeutic laparoscopy have been applied to the arena of colorectal surgery. A case is presented that combines these two modalities in a patient with colon cancer, laparoscopic mobilization of the large bowel, exteriorized resection, and BAR anastomosis.

Pancreatic necrosis is a well-known risk factor for infectious complications in the patients affected with acute pancreatitis. Dynamic CT with i.v. administration of a large bolus of contrast medium can establish the diagnosis of necrotizing pancreatitis. A series of 49 cases of severe acute pancreatitis was reviewed, and early CT investigations were seen to fail to detect pancreatic necrosis in 22 instances, versus 27 positive cases. In the group of patients with no necrosis, the clinical course was uneventful or characterized by mild complications which regressed spontaneously or by means of adjuvant medical treatment. On the contrary, 17 patients with necrotizing pancreatitis developed severe complications requiring intensive treatment. These complications occurred in 50% of the patients with < 50% of pancreatic necrosis, while the figure rose to 77% whenever more extensive involvement was observed. Our results show that the presence and extent of pancreatic necrosis must be diagnosed as early as possible for prognostic and therapeutic purposes; this can be done by the routinary use of dynamic CT with the administration of large amounts of contrast media at high flow rates.

In a placebo-controlled study the effects on ventricular rate regulation and exercise performance of xamoterol, 100 mg two times a day and 200 mg two times a day, and slow-release verapamil, 240 mg once a day, were assessed in 21 patients with chronic atrial fibrillation. The mean ventricular rate from noon to 6:00 PM was 101 +/- 20 beats/min with placebo, 95 +/- 17 beats/min with xamoterol 100 mg two times a day (not significant), 90 +/- 16 beats/min with xamoterol 200 mg two times a day (p less than 0.001 vs placebo) and 78 +/- 19 beats/min with verapamil (p less than 0.001 vs each other treatment). The mean ventricular rate from midnight to 6:00 AM was 69 +/- 16 beats/min with placebo, increased with xamoterol 100 mg two times a day and 200 mg two times a day to 75 +/- 15 beats/min and 74 +/- 16 beats/min, respectively (p less than 0.001 vs placebo), but decreased with verapamil to 62 +/- 15 beats/min (p less than 0.001 vs each other treatment). The number of ventricular pauses greater than 2.0 seconds was increased by verapamil (p less than 0.05). All active treatments reduced exercise ventricular rates (p less than 0.001), but the decrease was more pronounced with verapamil. The anaerobic threshold was reached significantly earlier with verapamil than with placebo (72 +/- 32 W vs 79 +/- 37 W; p less than 0.01). Xamoterol is preferable to verapamil for treatment of patients with chronic atrial fibrillation who exhibit both bradycardia at rest and excessive tachycardia during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Desmoid tumors in various anatomic sites were treated in 4 females and 3 males, ranging in age from 16-50 years, during a 6-year period. In 5 the tumor was completely excised with free margins. In the other 2 excision was incomplete and the tumor recurred within a few months. Desmoid tumors have a marked tendency to local recurrence, and therefore should be widely excised. There is no evidence that adjuvant therapy has a place in the management of these tumors.

The influence of the permanent wear of rigid high Dk-lenses (nominal Dk 71 or 92) with elliptical geometry on the corneal endothelium was assessed. For this purpose the endothelium of 16 patients was compared by specular microscopy before and after the permanent wear. The wearing time of the lenses varied between 7 and 24 months. Computerized morphometric analysis of the photographs revealed that the variability in cell size (polymegathism) and in cell shape (pleomorphism) did not change during the wearing period. It is suggested that this is due to the high gas-permeability and the elliptical geometry of the contact lenses.

We report and discuss a patient with characteristics of Marfan syndrome associated with a bicuspid aortic valve, premature aging, and primary hypogonadism.

In previously published cases of subacute or sealed postinfarction rupture of the free left ventricular wall, the patients presented a clinical picture of sudden shock and tamponade. Our patient, a 64-year-old man, suffered renewed chest pain on the fourth postinfarction day and went into cardiogenic shock, which was pharmacologically reversible. There were no bed-side signs of tamponade and the ECG showed the pattern of acute pericarditis, both features in contrast to previously reported cases in the literature. Echocardiography demonstrated localized fluid in the pericardial sac and a puncture revealed non-coagulating blood. The patient was successfully operated on. At surgery a small rupture sealed by blood clots was demonstrated in the infarcted inferior wall of the left ventricle.

The incidence, clinical findings, location, etiology, clinical diagnosis, and surgical treatment of chondrosarcoma of the larynx are discussed. Important features in the diagnosis and treatment of a chondrosarcomatous tumor of the larynx are demonstrated in a case report. The patient's chief complaint was episodic shortness of breath occurring with increasing frequency over a period of 12 months. Her dyspnea progressed in severity until an emergency tracheotomy was required for airway control. CT scan documented the attachment of the tumor to the right posterior lateral wall of the cricoid cartilage. Direct laryngoscopy and biopsy were done to obtain tissue for diagnosis. The histopathological examination revealed low-grade chondrosarcoma. The tumor was removed totally with a wide-margin mucous membrane incision and careful curettement. A definite difference in the consistency of the tumor compared to normal cartilage allowed complete excision of the tumor with minimal sacrifice of healthy cricoid cartilage. This presentation emphasizes the conservative surgical removal of these tumors and notes how a curette can be used for this removal.