Rare labial ulcer related to the use of all-trans retinoic acid in a patient with acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). All-trans retinoic acid (ATRA) is the first-choice therapy for the treatment of this disease, but has been associated with side effects, the most serious of which is retinoic acid syndrome (RAS). RAS is characterized by unexplained fever, dyspnea, pulmonary infiltrate, leukocytosis and nephropathy. Genital ulcers have been described in some cases, but only two cases of oral ulcers related to this syndrome have been described in the literature. This paper describes the third case of oral ulceration related to ATRA in a 32-year-old white man with diagnosis of APL. Clinicians should know the side effects of ATRA and identify oral ulcers resulting from this therapy. The prompt identification of these ulcers enables the institution of appropriate treatment and can therefore contribute to continuation of the patient's cancer treatment.

A highly stable monolithic enhancement cavity for second harmonic generation in the ultraviolet.

We present a highly stable bow-tie power enhancement cavity for critical second harmonic generation (SHG) into the UV using a Brewster-cut ß-BaB2O4 (BBO) nonlinear crystal. The cavity geometry is suitable for all UV wavelengths reachable with BBO and can be modified to accommodate anti-reflection coated crystals, extending its applicability to the entire wavelength range accessible with non-linear frequency conversion. The cavity is length-stabilized using a fast general purpose digital PI controller based on the open source STEMlab 125-14 (formerly Red Pitaya) system acting on a mirror mounted on a fast piezo actuator. We observe 130 h uninterrupted operation without decay in output power at 313 nm. The robustness of the system has been confirmed by exposing it to accelerations of up to 1 g with less than 10% in-lock output power variations. Furthermore, the cavity can withstand 30 min of acceleration exposure at a level of 3 grms without substantial change in the SHG output power, demonstrating that the design is suitable for transportable setups.

Modulation of intestinal cell differentiation in growing pigs is dependent on the fiber source in the diet.

Feeding high-fiber diets decreases cost, but also caloric and nutritional efficiency by modifying intestinal morphology and function. We analyzed the changes in intestinal cell composition, nutrient transporters and receptors, and cell differentiation induced by fibers from different sources. Forty-six finishing pigs (BW 84 ± 7 kg) were fed 1 of 4 diets: corn-soybean (Control; = 12), 23% wheat straw (WS; = 11), 55% corn distillers dried grains with solubles (DDGS; = 11), and 30% soybean hulls (SBH; = 12). Pigs were fed 2 meals daily to an amount equivalent to 2.5% of initial BW for 14 d in metabolism cages. Ilea were collected for histological and gene expression analysis after euthanasia. Data were analyzed using the Kruskal-Wallis test followed by Dunn's multiple comparisons and differences considered significant when < 0.05. The enterocyte marker was increased ( < 0.03) by feeding SBH compared with Control and WS diets. Goblet cells presence was greater ( < 0.01) in pigs fed WS and DDGS compared with Control, and in pigs fed WS compared with SBH ( = 0.02). expression was greater ( < 0.05) in pigs fed DDGS and SBH compared with Control diet. No changes were observed for endocrine and Paneth cells markers, villus and crypt length, or proliferation index. Compared with the Control, gene expression of receptors for oligopeptides, calcium, glucose, fructose, , and and was increased ( < 0.05) by feeding WS and DDGS diets. Feeding SBH diet repressed ( < 0.005) the compared with WS and DDGS diets, while DDGS repressed ( = 0.02) its expression compared with Control. Pigs fed DDGS had reduced ( < 0.001) , and those fed SBH showed increased ( < 0.05) expression compared with WS and DDGS pigs. Feeding WS and DDGS diets induced ( < 0.01) the expression of stem cell marker r-spondin receptor (, while was reduced ( < 0.02) by feeding DDGS compared with Control. The expression of was induced ( < 0.05) by all fibers compared with Control. Transcription factors and were suppressed ( < 0.001) by WS and DDGS compared with Control. In conclusion, feeding diets containing WS and DDGS modulated intestinal differentiation by promoting goblet cells and altered expression of nutrient receptors and transporters in growing pigs, while feeding SBH had less effect.

Between-Batch Pharmacokinetic Variability Inflates Type I Error Rate in Conventional Bioequivalence Trials: A Randomized Advair Diskus Clinical Trial.

We previously demonstrated pharmacokinetic differences among manufacturing batches of a US Food and Drug Administration (FDA)-approved dry powder inhalation product (Advair Diskus 100/50) large enough to establish between-batch bio-inequivalence. Here, we provide independent confirmation of pharmacokinetic bio-inequivalence among Advair Diskus 100/50 batches, and quantify residual and between-batch variance component magnitudes. These variance estimates are used to consider the type I error rate of the FDA's current two-way crossover design recommendation. When between-batch pharmacokinetic variability is substantial, the conventional two-way crossover design cannot accomplish the objectives of FDA's statistical bioequivalence test (i.e., cannot accurately estimate the test/reference ratio and associated confidence interval). The two-way crossover, which ignores between-batch pharmacokinetic variability, yields an artificially narrow confidence interval on the product comparison. The unavoidable consequence is type I error rate inflation, to ∼25%, when between-batch pharmacokinetic variability is nonzero. This risk of a false bioequivalence conclusion is substantially higher than asserted by regulators as acceptable consumer risk (5%).

Direct Observation of Photoinduced Tautomerization in Single Molecules at a Metal Surface.

Molecular switches are of fundamental importance in nature, and light is an important stimulus to selectively drive the switching process. However, the local dynamics of a conformational change in these molecules remain far from being completely understood at the single-molecule level. Here, we report the direct observation of photoinduced tautomerization in single porphycene molecules on a Cu(111) surface by using a combination of low-temperature scanning tunneling microscopy and laser excitation in the near-infrared to ultraviolet regime. It is found that the thermodynamically stable trans configuration of porphycene can be converted to the metastable cis configuration in a unidirectional fashion by photoirradiation. The wavelength dependence of the tautomerization cross section exhibits a steep increase around 2 eV and demonstrates that excitation of the Cu d-band electrons and the resulting hot carriers play a dominant role in the photochemical process. Additionally, a pronounced isotope effect in the cross section (∼100) is observed when the transferred hydrogen atoms are substituted with deuterium, indicating a significant contribution of zero-point energy in the reaction. Combined with the study of inelastic tunneling electron-induced tautomerization with the STM, we propose that tautomerization occurs via excitation of molecular vibrations after photoexcitation. Interestingly, the observed cross section of ∼10(-19) cm(2) in the visible-ultraviolet region is much higher than that of previously studied molecular switches on a metal surface, for example, azobenzene derivatives (10(-23)-10(-22) cm(2)). Furthermore, we examined a local environmental impact on the photoinduced tautomerization by varying molecular density on the surface and find substantial changes in the cross section and quenching of the process due to the intermolecular interaction at high density.

[Dopamine receptors of the corneal epithelium and endothelium]. / Dopaminrezeptoren des Hornhautepithels und -endothels.

BACKGROUND: Dopamine is a major neurotransmitter and its two receptor subgroups, termed D1-like and D2-like receptors, are found both in the central and peripheral nervous systems. D1-like receptors signal through increases, D2-like receptors through decreases in cAMP production. Reports about the presence of dopamine receptors in the cornea are rare and inconsistant. The aim of this study was to examine if native bovine corneal epithelial and endothelial cells express dopamine receptors and whether these receptors belong to the D1-like or D2-like group. MATERIALS AND METHODS: Dopamine receptors were studied using polyclonal antibodies. The cAMP concentration after receptor stimulation with dopamine was determined by means of an enzyme immunoassay. RESULTS: In bovine corneal epithelium and endothelium immunohistochemical staining was positive for D1-like receptors but not for D2-like receptors. Stimulation of corneal D1-like receptors with dopamine revealed a dose-dependent increase of the intracellular cAMP concentration which was blocked by SCH23 390 (a selective D1-like antagonist). CONCLUSION: Our data demonstrate that bovine corneal epithelium and endothelium express a functional D1-like receptor positively coupled to adenylyl cyclase and cAMP production. However, at the present time the physiological role of this receptor remains a matter of speculation.

Non-alcoholic fatty liver disease impairs hippocampal-dependent memory in male rats.

Non-alcoholic fatty liver disease (NAFLD) is a disorder observed in children and adults characterized by an accumulation of liver fat (>5% wet weight) in the absence of excessive alcohol intake. NAFLD affects 10 to 30% of the American population and is the most common cause of liver disease in the United States. NAFLD leads to serious disturbances in cardiovascular and hormonal function; however, possible effects on brain function have been overlooked. The aims of the present study were to test whether diet-induced NAFLD impairs hippocampal-dependent memory and to determine whether any observed deficits are associated with changes in hippocampal insulin signaling or concentrations of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). Post-weanling male Sprague-Dawley rats were fed a high fructose (60% of calories) or control diet for 12 weeks and then trained and tested in a spatial water maze. NAFLD was confirmed with postmortem measures of liver mass and liver lipid concentrations. NAFLD did not affect acquisition of the spatial water maze, but did impair retention tested 48 h later. Specifically, both groups demonstrated similar decreases in latency to swim to the escape platform over training trials, but on the memory test NAFLD rats took longer to reach the platform and made fewer visits to the platform location than control diet rats. There were no differences between the groups in terms of insulin-stimulated phosphorylation of insulin receptor ß subunit (IR-ß) and protein kinase B (PKB/AKT) in hippocampal slices or hippocampal BDNF or IGF-1 concentrations. Thus, these data indicate that NAFLD impairs hippocampal-dependent memory function and that the deficit does not appear attributable to alterations in hippocampal insulin signaling or hippocampal BDNF or IGF-1 concentrations.

[Effect of brimonidine on central corneal thickness]. / Einfluss von Brimonidin auf die zentrale Hornhautdicke.

BACKGROUND: Brimonidine, an alpha-2 adrenoceptor agonist, is widely used in glaucoma treatment. Although it is known that it is quickly taken up by the cornea following topical administration and although it is well established that the cornea expresses alpha-2 adrenoceptors there are only few studies available on the impact brimonidine has on the cornea. The aim of the present study was to show if topical application of brimonidine leads to an interaction with corneal alpha-2 adrenoceptors in terms of an increase in central corneal thickness. MATERIALS AND METHODS: Ten healthy test persons (five female and five male subjects) - mean age 30 ± 7years - were tested in a pilot study. Measured were intraocular pressure, epithelial, stromal and endothelial thickness before as well as ten minutes, 24, 48, 72 and 96 hours after administration of brimonidine 0.1 % eye drops twice daily. To check the impact of this medication, sodium hyaluronate eye drops were administered to the other eye twice daily. RESULTS: Administration of brimonidine 0.1 % resulted in a reduction of intraocular pressure from an initial value of 17 ± 2 mmHg to 13 ± 4 mmHg after four days (p = 0.001) as well as an increase in total corneal thickness from 559 ± 8 µm from the time of the baseline examination to 581 ± 11 µm (p < 0.001), an increase of epithelial thickness from 61 ± 1 µm to 68 ± 7 µm (p = 0.008) and stromal thickness from 488 ± 8 µm to 503 ± 8 µm (p < 0.001) after two days each. Another two days later total corneal thickness was 566 ± 10 µm (p = 0.032), epithelial thickness 64 ± 3 µm (p = 0.104) and stromal thickness 492 ± 8 µm (p = 0.139), which means that the values had returned more or less to the initial values measured. In contrast, endothelial thickness did not vary following administration of brimonidine 0.1 % (p = 0.109). CONCLUSION: Topical administration of brimonidine 0.1 % results in a reversible increase in corneal thickness. The question as to whether this increase is of clinical significance has to be answered by larger studies.

[m4 muscarinic receptors of the cornea : muscarinic cholinoceptor-stimulated inhibition of the cAMP-PKA pathway in corneal epithelial and endothelial cells]. / m4-muskarinerge Rezeptoren der Hornhaut : Hemmung des kornealen cAMP-PKA-Signalweges durch Stimulation muskarinerger Cholinozeptoren.

BACKGROUND: Muscarinic cholinoceptors have been found in all types of ocular tissue, e.g. in corneal epithelium and endothelium. Latest research has focused only on the m5 cholinoceptor subtype. However, previous studies have also indicated the presence of m2 or m4 receptor subtypes in corneal tissue. The aim of this study was to show the decrease of intracellular cAMP formation and protein kinase A (PKA) activity after stimulation of m2 or m4 cholinoceptors in bovine corneal epithelial and endothelial cells. MATERIALS UND METHODS: Muscarinic cholinoceptors were studied using polyclonal antibodies. The cAMP concentration was determined with an enzyme immunoassay and PKA activity was estimated by the consumption of ATP. RESULTS: Immunocytochemistry, immunofluorescence and immunoblotting revealed the presence of the m4 muscarinic cholinoceptor subtype but not of the m2 receptor subtype in bovine corneal epithelial and endothelial cells. In bovine corneal epithelium and endothelium protein cAMP formation was decreased and PKA activity was inhibited by acetylcholine in a dose-dependent manner (p<0.001). CONCLUSION: The findings indicate that stimulation of m4 muscarinic cholinoceptors inhibits the cAMP-PKA pathway in corneal epithelial and endothelial cells resulting in decreased protein kinase A activity. Further work will be needed to clarify the physiological role of this signaling pathway in corneal epithelium and endothelium.

Mechanical behavior of nanocrystalline NaCl islands on Cu(111).

The mechanical response of ultrathin NaCl crystallites of nanometer dimensions upon manipulation with the tip of a scanning tunneling microscope (STM) is investigated, expanding STM manipulation to various nanostructuring modes of inorganic materials as cutting, moving, and cracking. In the light of theoretical calculations, our results reveal that atomic-scale NaCl islands can behave elastically and follow a classical Hooke's law. When the elastic limit of the nanocrystallites is reached, the STM tip induces atomic dislocations and consequently the regime of plastic deformation is entered. Our methodology is paving the way to understand the mechanical behavior and properties of other nanoscale materials.

A high fructose diet impairs spatial memory in male rats.

Over the past three decades there has been a substantial increase in the amount of fructose consumed by North Americans. Recent evidence from rodents indicates that hippocampal insulin signaling facilitates memory and excessive fructose consumption produces hippocampal insulin resistance. Based on this evidence, the present study tested the hypothesis that a high fructose diet would impair hippocampal-dependent memory. Adult male Sprague-Dawley rats (postnatal day 61) were fed either a control (0% fructose) or high fructose diet (60% of calories). Food intake and body mass were measured regularly. After 19 weeks, the rats were given 3 days of training (8 trials/day) in a spatial version of the water maze task, and retention performance was probed 48 h later. The high fructose diet did not affect acquisition of the task, but did impair performance on the retention test. Specifically, rats fed a high fructose diet displayed significantly longer latencies to reach the area where the platform had been located, made significantly fewer approaches to that area, and spent significantly less time in the target quadrant than did control diet rats. There was no difference in swim speed between the two groups. The retention deficits correlated significantly with fructose-induced elevations of plasma triglyceride concentrations. Consequently, the impaired spatial water maze retention performance seen with the high fructose diet may have been attributable, at least in part, to fructose-induced increases in plasma triglycerides.

Medications for chronic pain practical review.

This review is confined to the drug management of chronic pain, and is specifically adapted to the resource-poor environment and the HIV pandemic of sub-Saharan Africa. A brief classification of chronic pain is followed by a discussion of the different classes of medications in use, including those used in migraine. An approach to the rational drug management of neuropathic pain is presented. In conclusion some general principles for prescribing in this setting are derived.

[Effect of timolol on central corneal thickness and endothelial cell density]. / Einfluss von Timolol auf die zentrale Hornhautdicke und Endothelzelldichte.

BACKGROUND: The measurement of corneal thickness plays an increasing role in glaucoma screening and diagnosis. The influence of a variety of drugs on corneal thickness is well established. Especially for antiglaucomateous drugs this effect seems to be important. However, little is known about the influence of beta receptor antagonists on corneal thickness. The aim of this study was to provide evidence of the effect of timolol on central corneal thickness and endothelial cell density. MATERIALS AND METHODS: Ten healthy volunteers (five women and five men) with a mean age of 29 years (range 25 to 56 years) were examined in a double-blind, prospective and randomised pilot study. Intraocular pressure, corneal thickness and endothelial cell density was estimated before as well as fifteen minutes, 24, 48, 72 and 96 hours after application of timolol 0.5 % eye drops twice daily. The partner eye received sodium hyaluronate eye drops twice daily and served as a control. RESULTS: The application of timolol showed a decrease of intraocular pressure from initially 12 mmHg to 9 mmHg after four days (p = 0,0188) as well as an increase of corneal thickness from 537 microm to 557 microm after four days (p = 0,0659). There was no change of intraocular pressure (p = 0,9935) or corneal thickness (p = 0,9998) in the control eyes. There was also no effect of timolol (p = 0,2782) or sodium hyaluronate (p = 0,1940) on endothelial cell density. CONCLUSIONS: The study provides evidence of the influence of beta receptor antagonists on corneal thickness. This effect may be caused by receptor mediated influences on corneal ion and fluid transport. Further studies are needed to show if the increase of corneal thickness after application of topical timolol has clinical importance.

Endogenous insulin signaling protects cultured neurons from oxygen-glucose deprivation-induced cell death.

Curiosity surrounding the physiological relevance of neural insulin signaling has gradually developed since the discovery that nervous tissue contains both the hormone and its receptor. Similar to other receptor tyrosine kinases, ligand interaction with the insulin receptor (IR) activates a variety of intracellular signaling pathways, particularly those relevant to cellular survival. Consequently, one explanation for the presence of the insulin pathway in the brain may involve participation in the response to neuronal injury. To investigate this possibility, the present study began by examining the effect of oxygen-glucose deprivation (OGD), a well-characterized in vitro model of ischemia, on ligand-binding, surface expression, and function of the IR in cultured rat neurons that were prepared under serum-free conditions. Reduced insulin-binding was observed following OGD, although surface expression of the receptor was not altered. However, OGD did significantly decrease the ability of insulin to stimulate phosphorylation of the transmembrane IR beta-subunit, without affecting protein expression of this subunit. Subsequent experiments focused on the manner in which pharmacologically manipulating IR function affected neuronal viability after OGD. Application of the IR sensitizer metformin moderately improved neuronal viability, while the specific IR tyrosine kinase inhibitor tyrphostin A47 was able to dramatically decrease viability; both compounds acted without affecting IR surface expression. Our study suggests that not only does the IR appear to play an important role in neuronal survival, but also that neurons may actively maintain IRs on the cell surface to compensate for the OGD-induced decrease in the ability of insulin to phosphorylate its receptor.

[Choroidal effusion syndrome after embolization of an indirect cavernous sinus fistula via the superior ophthalmic vein]. / Chorioidales Effusionssyndrom nach Embolisation einer indirekten Sinus-cavernosus-Fistel über die V. ophthalmica superior.

Embolization of a cavernous sinus fistula (SCF) via the superior ophthalmic vein (SOV) was reported to be an almost uncomplicated procedure, even after ligature of the vein at the end of the procedure. We report about a complication of this therapy. A 58-year-old female had a successful embolization of a right indirect cavernous sinus fistula via the SOV. At the end of the operation the SOV was ligated because of the danger of bleeding. Directly after surgery she experienced general worsening of the right eye with signs of venous congestion and marked effusion syndrome. The patient underwent total heparinization to achieve an opening of venous collaterals. Under local therapy with atropine 1% eye drops a decrease of the intraocular pressure was observed. The effusion syndrome was completely resolved within 1 month. If embolization of a cavernous sinus fistula is performed via the SOV, the ligature of the vein at the end of the procedure leads to thrombosis, which can reduce the venous stream from the eye and orbit. A secondary effusion syndrome with ocular hypertension because of a ciliolenticular block situation is possible and requires appropriate therapy. It is not possible to assess the capacity and time of opening of the venous collateral system before surgery. Therefore a transient outflow disturbance should be considered.

[Protein kinase C isoforms in corneal epithelium and endothelium]. / Proteinkinase C Isoformen in Hornhautepithel und -endothel.

BACKGROUND: Protein kinase C (PKC) plays a key role in cell metabolism. Three subgroups and 12 isoforms have been isolated so far, catalysing specific functions in cell metabolism. The demonstration of PKC subtypes in corneal tissue has been inconsistent. The aim of this study was to verify the expression of several PKC subgroups and isoforms in human and bovine corneal epithelial and endothelial cells. MATERIALS AND METHODS: PKC subgroups and isoforms were studied using polyclonal antibodies. RESULTS: Antibodies to PKC-alpha, -delta, -epsilon and -zeta, representing all three PKC subgroups, bound in human and bovine corneal epithelium and endothelium. No binding was found for antibodies to PKC-beta2. CONCLUSIONS: For the first time the presence of all three PKC subgroups was demonstrated in human and bovine corneal epithelial and endothelial cells. Further studies are needed to show the role of these subgroups in cellular functions such as cell proliferation and differentiation.

Epilepsy in sub-Saharan Africa: its socio-demography, aetiology, diagnosis and EEG characteristics in Harare, Zimbabwe.

OBJECTIVE: To assess epileptics with regard to socio-demographic characteristics, aetiology, EEG results and classification. DESIGN: A descriptive cohort study from 1997 to 2001. SETTING: Parirenyatwa Group of Hospitals in Harare, Zimbabwe. SUBJECTS: A total of 229 consecutive epileptic subjects. RESULTS: The mean (s.d.) follow-up was 3.2 (1.14) years. The mean (s.d.) age of subjects was 23.4(11.8) years and 56% of them were males, over one third (43.1%) were unemployed and had secondary education (48%). Over one fourth (26.6%) of the subjects were first borns and had a family history of epilepsy (25.8%). Most of the subjects had Generalised Tonic Clonic Seizures (TCS). Over half (51.5%) of the subjects had their first onset of seizures after the age of 20 years. Lack of sleep (7.9%) and emotional disturbance (5.4%) were described by subjects as the frequent provoking factors for epileptic attacks. One hundred and fourteen subjects had electroencephalogram (EEG) results. Of these, 96 (41.9%) subjects had abnormal EEG results and only 18 (7.9%) had normal EEG results a majority (43.8%) of whom were of generalised slow waves. Majority of the subjects (52.8%) sought treatments from biomedical drugs, but some started with traditional herbs (20.5%) and then biomedical drugs, whereas others sought biomedical drugs then resorted to traditional herbs (20.1%). Phenobarbital and carbamazepine were taken by over 40% of the subjects. CONCLUSION: The findings of this study seem to suggest that these referrals to a specialised epilepsy outpatient clinic for further management may be attributed to socio cultural issues in our African settings about the actual nature of the condition, hence the delay in treatments and diagnosis of seizures as well as under diagnoses of non-epileptic seizure disorders that may lead to the condition becomes uncontrollable. Inexpensive drugs such as phenobarbital and phenytoin can be able to control most of the epileptic seizures, if they can be made available in primary health care centres.

[Epidemic keratoconjunctivitis. Detecting adenoviruses]. / Keratoconjunctivitis epidemica. Nachweis von Adenoviren.

OBJECTIVE: The validity of the 15-min adenovirus assay SAS Adenotest was evaluated compared with virus detection by polymerase chain reaction (PCR) from conjunctival swabs. METHODS: In 75 patients with assumed epidemic keratoconjunctivitis, adenovirus detection from conjunctival swabs was performed by the immunochromatographic assay SAS Adenotest and PCR. RESULTS: In 25 patients adenovirus was detected by PCR, 18 of whom were detected by the SAS Adenotest and 7 of whom were not. No false positive results occurred. Sensitivity was 72% and specificity was 100%. CONCLUSIONS: The results indicate that rapid adenovirus detection with the SAS Adenotest is a useful tool in early epidemic keratoconjunctivitis. An additional PCR should be performed when clinical symptoms persist for 5 days or more.