Translational Vision Science & Technology, Aug 10, 2020
Glaucoma is the world's most common cause of irreversible blindness, which makes early diagnosis,... more Glaucoma is the world's most common cause of irreversible blindness, which makes early diagnosis, with the goal of preserving vision, essential. The current medical intervention is to reduce intraocular pressure (IOP) to slow down progression of the disease. The main goal of this study was to test a novel handheld acoustic self-tonometer on humans. Methods: A sound pressure pulse generated by a loudspeaker causes the eye to vibrate. A pressure chamber is placed on the human orbit to form a coupled system comprised of the patient's eye, the enclosed air, and the loudspeaker. A displacement sensor in front of the loudspeaker membrane allows the dynamic behavior of the entire system to be detected. Results: For this clinical trial series, a prototype of the acoustic self-tonometer principle was applied. The resulting membrane oscillation data showed sensitivity of patient IOP, but direct allocation of the measured damping and frequency to the IOP was not significant. For this reason, an artificial neural network was used to find relationships among the subjects' biometric eye parameters in combination with the self-tonometer data for the IOP reference. An expanded measurement uncertainty (k p = 2) equal to 6.53 mm Hg was determined for the self-tonometer in a Bland-Altman analysis using Goldmann applanation tonometer reference measurements. Conclusions: The usability and success rate of producing valid measurement values with the device during self-measurements by test subjects was nearly 92%. The crosssensitivities observed require compensation in a possible redesign phase to reduce the measurement uncertainty by at least 25% to the maximum of 5 mm Hg required to seek medical device approval. Translational Relevance: Building on successful laboratory experiments with pig eyes, this article reports the results of testing the acoustic tonometer on humans.
Journal of Sensors and Sensor Systems, Mar 5, 2018
Although glaucoma is currently the world's most common cause of irreversible blindness, there is ... more Although glaucoma is currently the world's most common cause of irreversible blindness, there is no curative therapy available to date. The major risk factor that can be influenced in order to stop disease progression is the eye pressure (IOP). Therefore early diagnosis of an altered IOP is essential for the goal of preserving vision. A novel IOP measurement principle for a handheld noncontact self-tonometer shall be validated. The measurement principle uses a pressure pulse generated by a loudspeaker to cause vibrations of the eye. In order to reach the required sound pressure, a closed pressure chamber is placed on the human orbit. With a microphone and a displacement sensor the dynamic behavior of the entire system is detected. In this article the abovementioned principle is being analyzed on porcine eyes under laboratory conditions. The combination of the loudspeaker, the pressure chamber, and the eye to be measured can be described as a coupled spring-mass-damper system. It is demonstrated for enucleated porcine eyes that a defined IOP variation leads to a change in the system's damping ratio. Considering only stochastic deviations, the derived standard uncertainty for the determination of the IOP amounts to < 1 mmHg in the physiological range. The in vitro measurements on porcine eyes help the understanding of the underlying physics and demand for further research on the influence of biometric parameters on eye vibrations. However, the laboratory results provide the basis for a gentle noncontact tonometry method with great applicational prospects. Data is currently being collected on human subjects in a clinical trial, to corroborate the measurement principle in vivo.
Zusammenfassung Ziel Ziel dieser Studie war es, die 2‑Jahres-Ergebnisse der filtrierenden Trabeku... more Zusammenfassung Ziel Ziel dieser Studie war es, die 2‑Jahres-Ergebnisse der filtrierenden Trabekulotomie (FTO) im Vergleich zur konventionellen Trabekulektomie (TE) bei primärem Offenwinkelglaukom, Pseudoexfoliationsglaukom und Pigmentglaukom zu untersuchen. Patienten und Methoden Es wurden 30 konsekutive Patienten nach FTO und 87 Patienten nach TE nach intraokularem Druck (IOD) und Alter im Verhältnis 1:3 gematcht. Primärer Endpunkt war das Erreichen des Zieldrucks nach 2 Jahren. Als vollständiger Erfolg wurde ein IOD ohne Medikamente von ≤ 18 mm Hg bei gleichzeitiger IOD-Reduktion um ≥ 30 % definiert, als qualifizierter Erfolg, wenn hierfür zusätzlich Medikamente erforderlich waren. Sekundäre Endpunkte waren mittlere Drucksenkung, resultierende Sehschärfe, Komplikationen und nachfolgende Operationen. Die Operationstechnik der filtrierenden Trabekulotomie ist als Video zu diesem Beitrag abrufbar. Ergebnisse Zwei-Jahres-Daten konnten von 27 Patienten aus der FTO-Gruppe und 68 Patien...
Translational Vision Science & Technology, 2020
Glaucoma is the world's most common cause of irreversible blindness, which makes early diagnosis,... more Glaucoma is the world's most common cause of irreversible blindness, which makes early diagnosis, with the goal of preserving vision, essential. The current medical intervention is to reduce intraocular pressure (IOP) to slow down progression of the disease. The main goal of this study was to test a novel handheld acoustic self-tonometer on humans. Methods: A sound pressure pulse generated by a loudspeaker causes the eye to vibrate. A pressure chamber is placed on the human orbit to form a coupled system comprised of the patient's eye, the enclosed air, and the loudspeaker. A displacement sensor in front of the loudspeaker membrane allows the dynamic behavior of the entire system to be detected. Results: For this clinical trial series, a prototype of the acoustic self-tonometer principle was applied. The resulting membrane oscillation data showed sensitivity of patient IOP, but direct allocation of the measured damping and frequency to the IOP was not significant. For this reason, an artificial neural network was used to find relationships among the subjects' biometric eye parameters in combination with the self-tonometer data for the IOP reference. An expanded measurement uncertainty (k p = 2) equal to 6.53 mm Hg was determined for the self-tonometer in a Bland-Altman analysis using Goldmann applanation tonometer reference measurements. Conclusions: The usability and success rate of producing valid measurement values with the device during self-measurements by test subjects was nearly 92%. The crosssensitivities observed require compensation in a possible redesign phase to reduce the measurement uncertainty by at least 25% to the maximum of 5 mm Hg required to seek medical device approval. Translational Relevance: Building on successful laboratory experiments with pig eyes, this article reports the results of testing the acoustic tonometer on humans.
Although glaucoma is currently the world's most common cause of irreversible blindness, there is ... more Although glaucoma is currently the world's most common cause of irreversible blindness, there is no curative therapy available to date. The major risk factor that can be influenced in order to stop disease progression is the eye pressure (IOP). Therefore early diagnosis of an altered IOP is essential for the goal of preserving vision. A novel IOP measurement principle for a handheld noncontact self-tonometer shall be validated. The measurement principle uses a pressure pulse generated by a loudspeaker to cause vibrations of the eye. In order to reach the required sound pressure, a closed pressure chamber is placed on the human orbit. With a microphone and a displacement sensor the dynamic behavior of the entire system is detected. In this article the abovementioned principle is being analyzed on porcine eyes under laboratory conditions. The combination of the loudspeaker, the pressure chamber, and the eye to be measured can be described as a coupled spring-mass-damper system. It is demonstrated for enucleated porcine eyes that a defined IOP variation leads to a change in the system's damping ratio. Considering only stochastic deviations, the derived standard uncertainty for the determination of the IOP amounts to < 1 mmHg in the physiological range. The in vitro measurements on porcine eyes help the understanding of the underlying physics and demand for further research on the influence of biometric parameters on eye vibrations. However, the laboratory results provide the basis for a gentle noncontact tonometry method with great applicational prospects. Data is currently being collected on human subjects in a clinical trial, to corroborate the measurement principle in vivo.
Charcot-Marie-Tooth type 1 neuropathies are inherited disorders of the peripheral nervous system ... more Charcot-Marie-Tooth type 1 neuropathies are inherited disorders of the peripheral nervous system caused by mutations in Schwann cell-related genes. Typically, no causative cure is presently available. Previous preclinical data of our group highlight the low grade, secondary inflammation common to distinct Charcot-Marie-Tooth type 1 neuropathies as a disease amplifier. In the current study, we have tested one of several available clinical agents targeting macrophages through its inhibition of the colony stimulating factor 1 receptor (CSF1R). We here show that in two distinct mouse models of Charcot-Marie-Tooth type 1 neuropathies, the systemic short-and long-term inhibition of CSF1R by oral administration leads to a robust decline in nerve macrophage numbers by $70% and substantial reduction of the typical histopathological and functional alterations. Interestingly, in a model for the dominant X-linked form of Charcot-Marie-Tooth type 1 neuropathy, the second most common form of the inherited neuropathies, macrophage ablation favours maintenance of axonal integrity and axonal resprouting, leading to preserved muscle innervation, increased muscle action potential amplitudes and muscle strengths in the range of wild-type mice. In another model mimicking a mild, demyelination-related Charcot-Marie-Tooth type 1 neuropathy caused by reduced P0 (MPZ) gene dosage, macrophage blockade causes an improved preservation of myelin, increased muscle action potential amplitudes, improved nerve conduction velocities and ameliorated muscle strength. These observations suggest that disease-amplifying macrophages can produce multiple adverse effects in the affected nerves which likely funnel down to common clinical features. Surprisingly, treatment of mouse models mimicking Charcot-Marie-Tooth type 1A neuropathy also caused macrophage blockade, but did not result in neuropathic or clinical improvements, most likely due to the late start of treatment of this early onset disease model. In summary, our study shows that targeting peripheral nerve macrophages by an orally administered inhibitor of CSF1R may offer a highly efficacious and safe treatment option for at least two distinct forms of the presently non-treatable Charcot-Marie-Tooth type 1 neuropathies.
Mucotomy is one of the most frequently applied surgical techniques for the management of inferior... more Mucotomy is one of the most frequently applied surgical techniques for the management of inferior turbinate hyperplasia. Mucotomy guarantees patent airway, however, it might lead to the emergence of sicca syndrome. In contrast, KTP (potassium titanyl phosphate) laser treatment spares the medial part of the inferior turbinate mucosa, contributing to maintenance of physiological nasal function. A retrospective comparative clinical study was performed to reveal the advantages and side-effects of both surgical methods in medium-and long-term in allergic rhinitis and non-allergic patients. Furthermore, we wished to determine the exact indications of the up-to-date laser treatment. Ninety-one of the 117 patients who underwent bilateral turbinate surgery during an 8-year period (2000-2007) responded to our questionnaire focusing on subjective postoperative changes. Patients were separated into 6 groups, based on the type of operation they underwent, the length of the follow-up and whether they suffered from allergies. The major complaint, nasal obstruction, improved in all 6 groups, which reached significance (p 0.05) in 4 groups. The most pronounced improvement was observed in the group of non-allergic patients with medium-term follow-up who underwent mucotomy. Nevertheless, a serious sideeffect: crusting also increased significantly (p 0.05) in the latter group, while it was absent in allergic patients with medium-term follow-up, who underwent mucotomy. These results lead us to propose the following protocol for the treatment of inferior turbinate hyperplasia: 1) after unsuccessful conservative treatment, laser treatment is suggested for non-allergic patients; 2) following unsuccessful conservative and even repeated laser treatment in the allergic group, mucotomy or turbinoplasty should be attempted.
CMT1B is the second most frequent autosomal dominant inherited neuropathy and is caused by assort... more CMT1B is the second most frequent autosomal dominant inherited neuropathy and is caused by assorted mutations of the myelin protein zero (MPZ) gene. MPZ mutations cause neuropathy gain of function mechanisms that are largely independent MPZs normal role of mediating myelin compaction. Whether there are only a few or multiple pathogenic mechanisms that cause CMT1B is unknown. Arg98Cys and Ser63Del MPZ are two CMT1B causing mutations that have been shown to cause neuropathy in mice at least in part by activating the unfolded protein response (UPR). We have recently treated Arg98Cys mice with derivatives of curcumin that improved the neuropathy and reduced UPR activation.(1) Future studies will address whether manipulating the UPR will be a common or rare strategy for treating CMT1B or other forms of inherited neuropathies.
Charcot-Marie-Tooth disease (CMT) disease encompasses a genetically heterogeneous group of inheri... more Charcot-Marie-Tooth disease (CMT) disease encompasses a genetically heterogeneous group of inherited neuropathies, also known as hereditary motor and sensory neuropathies. CMT results from mutations in more than 40 genes expressed in Schwann cells and neurons causing overlapping phenotypes. The classic CMT phenotype reflects length-dependent axonal degeneration characterized by distal sensory loss and weakness, deep tendon reflex abnormalities, and skeletal deformities. Recent articles have provided insight into the molecular pathogenesis of CMT, which, for the first time, suggest potential therapeutic targets. Although there are currently no effective medications for CMT, multiple clinical trials are ongoing or being planned. This review will focus on the underlying pathomechanisms and diagnostic approaches of CMT and discuss the emerging therapeutic strategies.
Mutations in MPZ cause CMT1B, the second most frequent cause of CMT1. Elegant studies with Ser63d... more Mutations in MPZ cause CMT1B, the second most frequent cause of CMT1. Elegant studies with Ser63del mice suggest that Ser63del MPZ is retained in the ER where it activates the unfolded protein response (UPR) that contributes to the neuropathy. Clinical information about patients with this mutation is limited. We present clinical and electrophysiological data on a large multigenerational family with CMT1B caused by Ser63del MPZ. The patients have a classical CMT1 phenotype that is much less severe than that of patients with Arg98Cys MPZ that also activates the UPR. These results suggest that clinical presentation along cannot predict which MPZ mutations will be retained in the ER and activate the UPR.
Brain white matter hyperintensities are more prevalent in migraine patients than in the general p... more Brain white matter hyperintensities are more prevalent in migraine patients than in the general population, but the pathogenesis and the risk factors of these hyperintensities are not fully elucidated. The authors analyzed the routine clinical data of 186 migraine patients who were referred to the Outpatient Headache Department of the
A tonsillectomiát követő legsúlyosabb komplikáció az utóvérzés. Primer post-tonsillectomiás vérzé... more A tonsillectomiát követő legsúlyosabb komplikáció az utóvérzés. Primer post-tonsillectomiás vérzésről akkor beszélünk, ha az a műtétet követően a nem megfelelően ellátott artériák vérzése miatt 24 órán belül fordul elő. Szekunder post-tonsillectomiás vérzés esetében a komplikáció az 1–10. posztoperatív nap egyikén, legnagyobb gyakorisággal az 5–8. napon jelentkezik. A szekunder vérzések rizikófaktorait illetően az irodalom rendkívül ellentmondásos. Célkitűzés: A szerzők azt a kérdést vizsgálták, hogy a rejtett coagulopathiáknak van-e oki szerepe a post-tonsillectomiás vérzésekben, valamint hogy a műtét előtti általános hematológiai szűrésnek van-e létjogosultsága. Módszer: Vizsgálataik során a 2002 és 2004 között a PTE Fül-orr-gégészeti és Fej-nyaksebészeti Klinikájára utóvérzés miatt felvett 115 beteg közül 107 esetben (59 nő, 48 férfi, átlagéletkor 29 év ± 10,9 év) kezdeményeztek utánvizsgálatot a thrombocytaszám, a vérzési idő, a trombinidő (TI), az aktivált parciális tromboplasz...
BACKGROUND. Chronic rhinosinusitis (CRS) affects 1-4% of the adult population. The etiology of th... more BACKGROUND. Chronic rhinosinusitis (CRS) affects 1-4% of the adult population. The etiology of this multifactorial, chronic disease, which leads to a significant impairment of the quality of life, often accompanied by nasal polyposis, is not fully understood. In the past decade, it was presumed that the disease, which causes characteristic eosinophilic infilltration of the nasal mucosa, is triggered by an enhanced (but not classical allergic IgE-type) immune response against fungal organisms in the nasal mucus. If this supposition is correct, then it appears obvious that the administration of amphotericin B nasal spray in adequate concentration following endoscopic polypectomy should be advantageous for these patients, and might even reduce the number of recurrent cases. MATERIAL AND METHODS. To check on this assumption, we conducted a prospective randomized placebo-controlled trial involving 33 patients, 30 of whom remained in the study throughout. Patients with nasal polyposis were operated on with an endoscopic technique between 1 November 2005 and 1 October 2006; group A (14 randomly selected patients) were treated with a nasal spray containing 5 mg/ ml amphotericin B, while the placebo group B (16 randomly selected patients) received a nasal spray lacking amphotericin B. We evaluated our results with the aid of a modified Lund-Mackay CT score, the SNAQ-11 test (which assesses changes in the symptoms), a quality of life test and endoscopy. The SPSS 14.0 for Windows program was utilized to process the data of examinations performed preoperatively and one year postoperatively. RESULTS. The CT scores of the group A patients one year after the operation exhibited wide scattering, without signs of recovery. The CT scores of the group B patients indicated a slight improvement, though this did not prove significant relative to group A. Both the SNAQ-11 test and the quality of life test revealed a significant improvement in each group, but the degrees of change in these tests did not differ significantly between the two groups of patients. The endoscopic findings indicated a slight improvement to the advantage of the amphotericin B-treated group 12 months after the operation. CONCLUSIONS. These results lead to the conclusion that the administration of amphotericin B nasal spray to patients operated on for nasal polyposis does not give rise to a significant alteration in either CT score, clinical symptoms, or quality of life. The more favorable clinical aspects observed in the amphotericin B-treated group during the endoscopic follow-up did not correspond to an improvement in the symptoms. In connection with the conclusions drawn from this study, the authors discuss the controversial data available on the fungal etiology of CRS. They critically analyze the contradictory observations and conclusions of seven recent clinical studies.
Mutations in myelin protein zero (MPZ) cause Charcot-Marie-Tooth disease type 1B. Many dominant M... more Mutations in myelin protein zero (MPZ) cause Charcot-Marie-Tooth disease type 1B. Many dominant MPZ mutations, including R98C, present as infantile onset dysmyelinating neuropathies. We have generated an R98C 'knock-in' mouse model of Charcot-Marie-Tooth type 1B, where a mutation encoding R98C was targeted to the mouse Mpz gene. Both heterozygous (R98C/ +) and homozygous (R98C/R98C) mice develop weakness, abnormal nerve conduction velocities and morphologically abnormal myelin; R98C/R98C mice are more severely affected. MpzR98C is retained in the endoplasmic reticulum of Schwann cells and provokes a transitory, canonical unfolded protein response. Ablation of Chop, a mediator of the protein kinase RNA-like endoplasmic reticulum kinase unfolded protein response pathway restores compound muscle action potential amplitudes of R98C/ + mice but does not alter the reduced conduction velocities, reduced axonal diameters or clinical behaviour of these animals. R98C/R98C Schwann cells are developmentally arrested in the promyelinating stage, whereas development is delayed in R98C/ + mice. The proportion of cells expressing c-Jun, an inhibitor of myelination, is elevated in mutant nerves, whereas the proportion of cells expressing the promyelinating transcription factor Krox-20 is decreased, particularly in R98C/R98C mice. Our results
Tooth disease type 1B is caused by mutations in myelin protein zero. R98C mice, an authentic mode... more Tooth disease type 1B is caused by mutations in myelin protein zero. R98C mice, an authentic model of early onset Charcot-Marie-Tooth disease type 1B, develop neuropathy in part because the misfolded mutant myelin protein zero is retained in the endoplasmic reticulum where it activates the unfolded protein response. Because oral curcumin, a component of the spice turmeric, has been shown to relieve endoplasmic reticulum stress and decrease the activation of the unfolded protein response, we treated R98C mutant mice with daily gastric lavage of curcumin or curcumin derivatives starting at 4 days of age and analysed them for clinical disability, electrophysiological parameters and peripheral nerve morphology. Heterozygous R98C mice treated with curcumin dissolved in sesame oil or phosphatidylcholine curcumin performed as well as wild-type littermates on a rotarod test and had increased numbers of large-diameter axons in their sciatic nerves. Treatment with the latter two compounds also increased compound muscle action potential amplitudes and the innervation of neuromuscular junctions in both heterozygous and homozygous R98C animals, but it did not improve nerve conduction velocity, myelin thickness, G-ratios or myelin period. The expression of c-Jun and suppressed cAMP-inducible POU (SCIP)-transcription factors that inhibit myelination when overexpressed-was also decreased by treatment. Consistent with its role in reducing endoplasmic reticulum stress, treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin was associated with decreased X-box binding protein (XBP1) splicing. Taken together, these data demonstrate that treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin improves the peripheral neuropathy of R98C mice by alleviating endoplasmic reticulum stress, by reducing the activation of unfolded protein response and by promoting Schwann cell differentiation.
Graefes Archive for Clinical and Experimental Ophthalmology, Nov 30, 2023
Aim Migraine is a chronic neurovascular disease that affects the trigeminovascular system. The pu... more Aim Migraine is a chronic neurovascular disease that affects the trigeminovascular system. The purpose of this study was to evaluate corneal subbasal nerve fibers, dendritic cells and to measure tear film parameters in migraine. Patients and methods 87 eyes of 44 patients suffering from migraine with a mean age of 33.23 ± 11.41 years were included in our study. 25 age-matched controls (mean age of 30.16 ± 12.59 years; P = 0.162) were recruited. The corneal subbasal plexus and the dendritic cells (DC) were analyzed using in vivo confocal microscopy (Heidelberg Retina Tomograph II Rostock Cornea Module; Heidelberg Engineering GmbH), and the tear film was imaged using LacryDiag (Quantel Medical, France). Results Regarding the subbasal nerve fibers of the cornea, none of the examined parameters differed significantly in migraine patients from controls. We found a significant increase in the corneal DC density (P < 0.0001) and DC area (P < 0.0001) in migraine patients compared to healthy volunteers. DC density showed a positive correlation with the monthly attack frequency (r = 0.32, P = 0.041) and the DC area a negative correlation with corneal nerve branch density (r =-0.233, P = 0.039), nerve fiber length (r =-0.232, P = 0.04) and total branch density (r =-0.233, P = 0.039). Using LacryDiag a significant loss of Meibomian gland area could be detected on the superior eyelid (P = 0.005) in migraine. Conclusions Our results suggest the presence of neuroinflammation in the cornea of migraine patients affecting the peripheral trigeminal system. Dendritic cells surrounding the subbasal plexus may be involved in the activation and modulation of pain in migraine.
Translational Vision Science & Technology, Aug 10, 2020
Glaucoma is the world's most common cause of irreversible blindness, which makes early diagnosis,... more Glaucoma is the world's most common cause of irreversible blindness, which makes early diagnosis, with the goal of preserving vision, essential. The current medical intervention is to reduce intraocular pressure (IOP) to slow down progression of the disease. The main goal of this study was to test a novel handheld acoustic self-tonometer on humans. Methods: A sound pressure pulse generated by a loudspeaker causes the eye to vibrate. A pressure chamber is placed on the human orbit to form a coupled system comprised of the patient's eye, the enclosed air, and the loudspeaker. A displacement sensor in front of the loudspeaker membrane allows the dynamic behavior of the entire system to be detected. Results: For this clinical trial series, a prototype of the acoustic self-tonometer principle was applied. The resulting membrane oscillation data showed sensitivity of patient IOP, but direct allocation of the measured damping and frequency to the IOP was not significant. For this reason, an artificial neural network was used to find relationships among the subjects' biometric eye parameters in combination with the self-tonometer data for the IOP reference. An expanded measurement uncertainty (k p = 2) equal to 6.53 mm Hg was determined for the self-tonometer in a Bland-Altman analysis using Goldmann applanation tonometer reference measurements. Conclusions: The usability and success rate of producing valid measurement values with the device during self-measurements by test subjects was nearly 92%. The crosssensitivities observed require compensation in a possible redesign phase to reduce the measurement uncertainty by at least 25% to the maximum of 5 mm Hg required to seek medical device approval. Translational Relevance: Building on successful laboratory experiments with pig eyes, this article reports the results of testing the acoustic tonometer on humans.
Journal of Sensors and Sensor Systems, Mar 5, 2018
Although glaucoma is currently the world's most common cause of irreversible blindness, there is ... more Although glaucoma is currently the world's most common cause of irreversible blindness, there is no curative therapy available to date. The major risk factor that can be influenced in order to stop disease progression is the eye pressure (IOP). Therefore early diagnosis of an altered IOP is essential for the goal of preserving vision. A novel IOP measurement principle for a handheld noncontact self-tonometer shall be validated. The measurement principle uses a pressure pulse generated by a loudspeaker to cause vibrations of the eye. In order to reach the required sound pressure, a closed pressure chamber is placed on the human orbit. With a microphone and a displacement sensor the dynamic behavior of the entire system is detected. In this article the abovementioned principle is being analyzed on porcine eyes under laboratory conditions. The combination of the loudspeaker, the pressure chamber, and the eye to be measured can be described as a coupled spring-mass-damper system. It is demonstrated for enucleated porcine eyes that a defined IOP variation leads to a change in the system's damping ratio. Considering only stochastic deviations, the derived standard uncertainty for the determination of the IOP amounts to < 1 mmHg in the physiological range. The in vitro measurements on porcine eyes help the understanding of the underlying physics and demand for further research on the influence of biometric parameters on eye vibrations. However, the laboratory results provide the basis for a gentle noncontact tonometry method with great applicational prospects. Data is currently being collected on human subjects in a clinical trial, to corroborate the measurement principle in vivo.
Zusammenfassung Ziel Ziel dieser Studie war es, die 2‑Jahres-Ergebnisse der filtrierenden Trabeku... more Zusammenfassung Ziel Ziel dieser Studie war es, die 2‑Jahres-Ergebnisse der filtrierenden Trabekulotomie (FTO) im Vergleich zur konventionellen Trabekulektomie (TE) bei primärem Offenwinkelglaukom, Pseudoexfoliationsglaukom und Pigmentglaukom zu untersuchen. Patienten und Methoden Es wurden 30 konsekutive Patienten nach FTO und 87 Patienten nach TE nach intraokularem Druck (IOD) und Alter im Verhältnis 1:3 gematcht. Primärer Endpunkt war das Erreichen des Zieldrucks nach 2 Jahren. Als vollständiger Erfolg wurde ein IOD ohne Medikamente von ≤ 18 mm Hg bei gleichzeitiger IOD-Reduktion um ≥ 30 % definiert, als qualifizierter Erfolg, wenn hierfür zusätzlich Medikamente erforderlich waren. Sekundäre Endpunkte waren mittlere Drucksenkung, resultierende Sehschärfe, Komplikationen und nachfolgende Operationen. Die Operationstechnik der filtrierenden Trabekulotomie ist als Video zu diesem Beitrag abrufbar. Ergebnisse Zwei-Jahres-Daten konnten von 27 Patienten aus der FTO-Gruppe und 68 Patien...
Translational Vision Science & Technology, 2020
Glaucoma is the world's most common cause of irreversible blindness, which makes early diagnosis,... more Glaucoma is the world's most common cause of irreversible blindness, which makes early diagnosis, with the goal of preserving vision, essential. The current medical intervention is to reduce intraocular pressure (IOP) to slow down progression of the disease. The main goal of this study was to test a novel handheld acoustic self-tonometer on humans. Methods: A sound pressure pulse generated by a loudspeaker causes the eye to vibrate. A pressure chamber is placed on the human orbit to form a coupled system comprised of the patient's eye, the enclosed air, and the loudspeaker. A displacement sensor in front of the loudspeaker membrane allows the dynamic behavior of the entire system to be detected. Results: For this clinical trial series, a prototype of the acoustic self-tonometer principle was applied. The resulting membrane oscillation data showed sensitivity of patient IOP, but direct allocation of the measured damping and frequency to the IOP was not significant. For this reason, an artificial neural network was used to find relationships among the subjects' biometric eye parameters in combination with the self-tonometer data for the IOP reference. An expanded measurement uncertainty (k p = 2) equal to 6.53 mm Hg was determined for the self-tonometer in a Bland-Altman analysis using Goldmann applanation tonometer reference measurements. Conclusions: The usability and success rate of producing valid measurement values with the device during self-measurements by test subjects was nearly 92%. The crosssensitivities observed require compensation in a possible redesign phase to reduce the measurement uncertainty by at least 25% to the maximum of 5 mm Hg required to seek medical device approval. Translational Relevance: Building on successful laboratory experiments with pig eyes, this article reports the results of testing the acoustic tonometer on humans.
Although glaucoma is currently the world's most common cause of irreversible blindness, there is ... more Although glaucoma is currently the world's most common cause of irreversible blindness, there is no curative therapy available to date. The major risk factor that can be influenced in order to stop disease progression is the eye pressure (IOP). Therefore early diagnosis of an altered IOP is essential for the goal of preserving vision. A novel IOP measurement principle for a handheld noncontact self-tonometer shall be validated. The measurement principle uses a pressure pulse generated by a loudspeaker to cause vibrations of the eye. In order to reach the required sound pressure, a closed pressure chamber is placed on the human orbit. With a microphone and a displacement sensor the dynamic behavior of the entire system is detected. In this article the abovementioned principle is being analyzed on porcine eyes under laboratory conditions. The combination of the loudspeaker, the pressure chamber, and the eye to be measured can be described as a coupled spring-mass-damper system. It is demonstrated for enucleated porcine eyes that a defined IOP variation leads to a change in the system's damping ratio. Considering only stochastic deviations, the derived standard uncertainty for the determination of the IOP amounts to < 1 mmHg in the physiological range. The in vitro measurements on porcine eyes help the understanding of the underlying physics and demand for further research on the influence of biometric parameters on eye vibrations. However, the laboratory results provide the basis for a gentle noncontact tonometry method with great applicational prospects. Data is currently being collected on human subjects in a clinical trial, to corroborate the measurement principle in vivo.
Charcot-Marie-Tooth type 1 neuropathies are inherited disorders of the peripheral nervous system ... more Charcot-Marie-Tooth type 1 neuropathies are inherited disorders of the peripheral nervous system caused by mutations in Schwann cell-related genes. Typically, no causative cure is presently available. Previous preclinical data of our group highlight the low grade, secondary inflammation common to distinct Charcot-Marie-Tooth type 1 neuropathies as a disease amplifier. In the current study, we have tested one of several available clinical agents targeting macrophages through its inhibition of the colony stimulating factor 1 receptor (CSF1R). We here show that in two distinct mouse models of Charcot-Marie-Tooth type 1 neuropathies, the systemic short-and long-term inhibition of CSF1R by oral administration leads to a robust decline in nerve macrophage numbers by $70% and substantial reduction of the typical histopathological and functional alterations. Interestingly, in a model for the dominant X-linked form of Charcot-Marie-Tooth type 1 neuropathy, the second most common form of the inherited neuropathies, macrophage ablation favours maintenance of axonal integrity and axonal resprouting, leading to preserved muscle innervation, increased muscle action potential amplitudes and muscle strengths in the range of wild-type mice. In another model mimicking a mild, demyelination-related Charcot-Marie-Tooth type 1 neuropathy caused by reduced P0 (MPZ) gene dosage, macrophage blockade causes an improved preservation of myelin, increased muscle action potential amplitudes, improved nerve conduction velocities and ameliorated muscle strength. These observations suggest that disease-amplifying macrophages can produce multiple adverse effects in the affected nerves which likely funnel down to common clinical features. Surprisingly, treatment of mouse models mimicking Charcot-Marie-Tooth type 1A neuropathy also caused macrophage blockade, but did not result in neuropathic or clinical improvements, most likely due to the late start of treatment of this early onset disease model. In summary, our study shows that targeting peripheral nerve macrophages by an orally administered inhibitor of CSF1R may offer a highly efficacious and safe treatment option for at least two distinct forms of the presently non-treatable Charcot-Marie-Tooth type 1 neuropathies.
Mucotomy is one of the most frequently applied surgical techniques for the management of inferior... more Mucotomy is one of the most frequently applied surgical techniques for the management of inferior turbinate hyperplasia. Mucotomy guarantees patent airway, however, it might lead to the emergence of sicca syndrome. In contrast, KTP (potassium titanyl phosphate) laser treatment spares the medial part of the inferior turbinate mucosa, contributing to maintenance of physiological nasal function. A retrospective comparative clinical study was performed to reveal the advantages and side-effects of both surgical methods in medium-and long-term in allergic rhinitis and non-allergic patients. Furthermore, we wished to determine the exact indications of the up-to-date laser treatment. Ninety-one of the 117 patients who underwent bilateral turbinate surgery during an 8-year period (2000-2007) responded to our questionnaire focusing on subjective postoperative changes. Patients were separated into 6 groups, based on the type of operation they underwent, the length of the follow-up and whether they suffered from allergies. The major complaint, nasal obstruction, improved in all 6 groups, which reached significance (p 0.05) in 4 groups. The most pronounced improvement was observed in the group of non-allergic patients with medium-term follow-up who underwent mucotomy. Nevertheless, a serious sideeffect: crusting also increased significantly (p 0.05) in the latter group, while it was absent in allergic patients with medium-term follow-up, who underwent mucotomy. These results lead us to propose the following protocol for the treatment of inferior turbinate hyperplasia: 1) after unsuccessful conservative treatment, laser treatment is suggested for non-allergic patients; 2) following unsuccessful conservative and even repeated laser treatment in the allergic group, mucotomy or turbinoplasty should be attempted.
CMT1B is the second most frequent autosomal dominant inherited neuropathy and is caused by assort... more CMT1B is the second most frequent autosomal dominant inherited neuropathy and is caused by assorted mutations of the myelin protein zero (MPZ) gene. MPZ mutations cause neuropathy gain of function mechanisms that are largely independent MPZs normal role of mediating myelin compaction. Whether there are only a few or multiple pathogenic mechanisms that cause CMT1B is unknown. Arg98Cys and Ser63Del MPZ are two CMT1B causing mutations that have been shown to cause neuropathy in mice at least in part by activating the unfolded protein response (UPR). We have recently treated Arg98Cys mice with derivatives of curcumin that improved the neuropathy and reduced UPR activation.(1) Future studies will address whether manipulating the UPR will be a common or rare strategy for treating CMT1B or other forms of inherited neuropathies.
Charcot-Marie-Tooth disease (CMT) disease encompasses a genetically heterogeneous group of inheri... more Charcot-Marie-Tooth disease (CMT) disease encompasses a genetically heterogeneous group of inherited neuropathies, also known as hereditary motor and sensory neuropathies. CMT results from mutations in more than 40 genes expressed in Schwann cells and neurons causing overlapping phenotypes. The classic CMT phenotype reflects length-dependent axonal degeneration characterized by distal sensory loss and weakness, deep tendon reflex abnormalities, and skeletal deformities. Recent articles have provided insight into the molecular pathogenesis of CMT, which, for the first time, suggest potential therapeutic targets. Although there are currently no effective medications for CMT, multiple clinical trials are ongoing or being planned. This review will focus on the underlying pathomechanisms and diagnostic approaches of CMT and discuss the emerging therapeutic strategies.
Mutations in MPZ cause CMT1B, the second most frequent cause of CMT1. Elegant studies with Ser63d... more Mutations in MPZ cause CMT1B, the second most frequent cause of CMT1. Elegant studies with Ser63del mice suggest that Ser63del MPZ is retained in the ER where it activates the unfolded protein response (UPR) that contributes to the neuropathy. Clinical information about patients with this mutation is limited. We present clinical and electrophysiological data on a large multigenerational family with CMT1B caused by Ser63del MPZ. The patients have a classical CMT1 phenotype that is much less severe than that of patients with Arg98Cys MPZ that also activates the UPR. These results suggest that clinical presentation along cannot predict which MPZ mutations will be retained in the ER and activate the UPR.
Brain white matter hyperintensities are more prevalent in migraine patients than in the general p... more Brain white matter hyperintensities are more prevalent in migraine patients than in the general population, but the pathogenesis and the risk factors of these hyperintensities are not fully elucidated. The authors analyzed the routine clinical data of 186 migraine patients who were referred to the Outpatient Headache Department of the
A tonsillectomiát követő legsúlyosabb komplikáció az utóvérzés. Primer post-tonsillectomiás vérzé... more A tonsillectomiát követő legsúlyosabb komplikáció az utóvérzés. Primer post-tonsillectomiás vérzésről akkor beszélünk, ha az a műtétet követően a nem megfelelően ellátott artériák vérzése miatt 24 órán belül fordul elő. Szekunder post-tonsillectomiás vérzés esetében a komplikáció az 1–10. posztoperatív nap egyikén, legnagyobb gyakorisággal az 5–8. napon jelentkezik. A szekunder vérzések rizikófaktorait illetően az irodalom rendkívül ellentmondásos. Célkitűzés: A szerzők azt a kérdést vizsgálták, hogy a rejtett coagulopathiáknak van-e oki szerepe a post-tonsillectomiás vérzésekben, valamint hogy a műtét előtti általános hematológiai szűrésnek van-e létjogosultsága. Módszer: Vizsgálataik során a 2002 és 2004 között a PTE Fül-orr-gégészeti és Fej-nyaksebészeti Klinikájára utóvérzés miatt felvett 115 beteg közül 107 esetben (59 nő, 48 férfi, átlagéletkor 29 év ± 10,9 év) kezdeményeztek utánvizsgálatot a thrombocytaszám, a vérzési idő, a trombinidő (TI), az aktivált parciális tromboplasz...
BACKGROUND. Chronic rhinosinusitis (CRS) affects 1-4% of the adult population. The etiology of th... more BACKGROUND. Chronic rhinosinusitis (CRS) affects 1-4% of the adult population. The etiology of this multifactorial, chronic disease, which leads to a significant impairment of the quality of life, often accompanied by nasal polyposis, is not fully understood. In the past decade, it was presumed that the disease, which causes characteristic eosinophilic infilltration of the nasal mucosa, is triggered by an enhanced (but not classical allergic IgE-type) immune response against fungal organisms in the nasal mucus. If this supposition is correct, then it appears obvious that the administration of amphotericin B nasal spray in adequate concentration following endoscopic polypectomy should be advantageous for these patients, and might even reduce the number of recurrent cases. MATERIAL AND METHODS. To check on this assumption, we conducted a prospective randomized placebo-controlled trial involving 33 patients, 30 of whom remained in the study throughout. Patients with nasal polyposis were operated on with an endoscopic technique between 1 November 2005 and 1 October 2006; group A (14 randomly selected patients) were treated with a nasal spray containing 5 mg/ ml amphotericin B, while the placebo group B (16 randomly selected patients) received a nasal spray lacking amphotericin B. We evaluated our results with the aid of a modified Lund-Mackay CT score, the SNAQ-11 test (which assesses changes in the symptoms), a quality of life test and endoscopy. The SPSS 14.0 for Windows program was utilized to process the data of examinations performed preoperatively and one year postoperatively. RESULTS. The CT scores of the group A patients one year after the operation exhibited wide scattering, without signs of recovery. The CT scores of the group B patients indicated a slight improvement, though this did not prove significant relative to group A. Both the SNAQ-11 test and the quality of life test revealed a significant improvement in each group, but the degrees of change in these tests did not differ significantly between the two groups of patients. The endoscopic findings indicated a slight improvement to the advantage of the amphotericin B-treated group 12 months after the operation. CONCLUSIONS. These results lead to the conclusion that the administration of amphotericin B nasal spray to patients operated on for nasal polyposis does not give rise to a significant alteration in either CT score, clinical symptoms, or quality of life. The more favorable clinical aspects observed in the amphotericin B-treated group during the endoscopic follow-up did not correspond to an improvement in the symptoms. In connection with the conclusions drawn from this study, the authors discuss the controversial data available on the fungal etiology of CRS. They critically analyze the contradictory observations and conclusions of seven recent clinical studies.
Mutations in myelin protein zero (MPZ) cause Charcot-Marie-Tooth disease type 1B. Many dominant M... more Mutations in myelin protein zero (MPZ) cause Charcot-Marie-Tooth disease type 1B. Many dominant MPZ mutations, including R98C, present as infantile onset dysmyelinating neuropathies. We have generated an R98C 'knock-in' mouse model of Charcot-Marie-Tooth type 1B, where a mutation encoding R98C was targeted to the mouse Mpz gene. Both heterozygous (R98C/ +) and homozygous (R98C/R98C) mice develop weakness, abnormal nerve conduction velocities and morphologically abnormal myelin; R98C/R98C mice are more severely affected. MpzR98C is retained in the endoplasmic reticulum of Schwann cells and provokes a transitory, canonical unfolded protein response. Ablation of Chop, a mediator of the protein kinase RNA-like endoplasmic reticulum kinase unfolded protein response pathway restores compound muscle action potential amplitudes of R98C/ + mice but does not alter the reduced conduction velocities, reduced axonal diameters or clinical behaviour of these animals. R98C/R98C Schwann cells are developmentally arrested in the promyelinating stage, whereas development is delayed in R98C/ + mice. The proportion of cells expressing c-Jun, an inhibitor of myelination, is elevated in mutant nerves, whereas the proportion of cells expressing the promyelinating transcription factor Krox-20 is decreased, particularly in R98C/R98C mice. Our results
Tooth disease type 1B is caused by mutations in myelin protein zero. R98C mice, an authentic mode... more Tooth disease type 1B is caused by mutations in myelin protein zero. R98C mice, an authentic model of early onset Charcot-Marie-Tooth disease type 1B, develop neuropathy in part because the misfolded mutant myelin protein zero is retained in the endoplasmic reticulum where it activates the unfolded protein response. Because oral curcumin, a component of the spice turmeric, has been shown to relieve endoplasmic reticulum stress and decrease the activation of the unfolded protein response, we treated R98C mutant mice with daily gastric lavage of curcumin or curcumin derivatives starting at 4 days of age and analysed them for clinical disability, electrophysiological parameters and peripheral nerve morphology. Heterozygous R98C mice treated with curcumin dissolved in sesame oil or phosphatidylcholine curcumin performed as well as wild-type littermates on a rotarod test and had increased numbers of large-diameter axons in their sciatic nerves. Treatment with the latter two compounds also increased compound muscle action potential amplitudes and the innervation of neuromuscular junctions in both heterozygous and homozygous R98C animals, but it did not improve nerve conduction velocity, myelin thickness, G-ratios or myelin period. The expression of c-Jun and suppressed cAMP-inducible POU (SCIP)-transcription factors that inhibit myelination when overexpressed-was also decreased by treatment. Consistent with its role in reducing endoplasmic reticulum stress, treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin was associated with decreased X-box binding protein (XBP1) splicing. Taken together, these data demonstrate that treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin improves the peripheral neuropathy of R98C mice by alleviating endoplasmic reticulum stress, by reducing the activation of unfolded protein response and by promoting Schwann cell differentiation.
Graefes Archive for Clinical and Experimental Ophthalmology, Nov 30, 2023
Aim Migraine is a chronic neurovascular disease that affects the trigeminovascular system. The pu... more Aim Migraine is a chronic neurovascular disease that affects the trigeminovascular system. The purpose of this study was to evaluate corneal subbasal nerve fibers, dendritic cells and to measure tear film parameters in migraine. Patients and methods 87 eyes of 44 patients suffering from migraine with a mean age of 33.23 ± 11.41 years were included in our study. 25 age-matched controls (mean age of 30.16 ± 12.59 years; P = 0.162) were recruited. The corneal subbasal plexus and the dendritic cells (DC) were analyzed using in vivo confocal microscopy (Heidelberg Retina Tomograph II Rostock Cornea Module; Heidelberg Engineering GmbH), and the tear film was imaged using LacryDiag (Quantel Medical, France). Results Regarding the subbasal nerve fibers of the cornea, none of the examined parameters differed significantly in migraine patients from controls. We found a significant increase in the corneal DC density (P < 0.0001) and DC area (P < 0.0001) in migraine patients compared to healthy volunteers. DC density showed a positive correlation with the monthly attack frequency (r = 0.32, P = 0.041) and the DC area a negative correlation with corneal nerve branch density (r =-0.233, P = 0.039), nerve fiber length (r =-0.232, P = 0.04) and total branch density (r =-0.233, P = 0.039). Using LacryDiag a significant loss of Meibomian gland area could be detected on the superior eyelid (P = 0.005) in migraine. Conclusions Our results suggest the presence of neuroinflammation in the cornea of migraine patients affecting the peripheral trigeminal system. Dendritic cells surrounding the subbasal plexus may be involved in the activation and modulation of pain in migraine.
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Papers by Ágnes Patzkó