2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase.

A series of substituted 2-iminopyrrolidines has been prepared and shown to be potent and selective inhibitors of the human inducible nitric oxide synthase (hiNOS) isoform versus the human endothelial nitric oxide synthase (heNOS) and the human neuronal nitric oxide synthase (hnNOS). Simple substitutions at the 3-, 4-, or 5-position afforded more potent analogues than the parent 2-iminopyrrolidine 1. The effect of ring substitutions on both potency and selectivity for the different NOS isoforms is described. Substitution at the 4- and 5-positions of the 2-iminopyrrolidine yielded both potent and selective inhibitors of hiNOS. In particular, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine, monohydrochloride (20), displayed potent inhibition of hiNOS (IC50 = 0.25 microM) and selectivities of 897 (heNOS IC50/hiNOS IC50) and 13 (hnNOS IC50/hiNOS IC50). Example 20 was shown to be an efficacious inhibitor of NO production in the mouse endotoxin assay. Furthermore, 20 displayed in vivo selectivity, versus heNOS isoform, by not elevating blood pressure at multiples of the effective dose in the mouse.

In vivo efficacy of two heated humidifiers used during CPAP-therapy for obstructive sleep apnea under various environmental conditions.

STUDY OBJECTIVES: To investigate the humidification performance-defined as the maximum achievable absolute humidity in the CPAP tube-of two heated humidifier systems (HH) offered as CPAP accessories, as a function of ambient air conditions. DESIGN: In 48 patients undergoing CPAP treatment, temperature (T) and relative humidity (RH) in the distal CPAP tube system were measured, with and without either of the two heated humidifiers A (HH-A, n=23), or B (HH-B, n=25), until a steady state was achieved. At the same time, ambient T and RH in the examination room were recorded. T and RH were used to calculate the absolute humidity (AH). SETTING: University Hospital, Erlangen, Germany. PATICIPANTS: 48 patients with obstructive sleep apnea undergoing CPAP therapy. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Conditions in the examination room during measurement with the HH-A, T = 22.5+2.1 (16.4-26.0) degrees C and AH = 9.3+2.4 (5.3-13.9) g/m3 did not differ significantly from those prevailing during measurements with the HH-B, T = 22.9+1.9 (18.9-26.3) degrees C and AH = 9.9+2.8 (6.2-16.4) g/m3. The mean humidification performance (steady state AH with HH within the CPAP tube) of the HH-A was 23.5+2.9 (19.1-29.9) g/m3, that of the HH-B 26.8+3.9 (21.0-34.4) g/m3. CONCLUSIONS: Under the ambient conditions of humidity and temperature, commonly found in European and North American bedrooms, both HH demonstrate a high humidification performance that even falls within the range recommended for intubated patients. The difference between the two HH is small, and probably not clinical relevant. Thus, it would appear that both HH are suitable for the treatment of dry upper airways under CPAP therapy.

Role of nucleotide sugar pools in the inhibition of NCAM polysialylation by ammonia.

Ammonia in animal cell cultures has been shown to specifically inhibit terminal sialylation of N- and O-linked oligosaccharides of glycoproteins. For example, we have previously shown that as little as 2.5 mM NH4Cl can decrease neural cell adhesion molecule (NCAM) polysialylation in both small cell lung cancer (SCLC) and Chinese hamster ovary (CHO) cells. Besides its potential involvement in SCLC metastasis, polysialic acid (PolySia) is a sensitive marker for measuring changes in sialylation. The role of UDP-N-acetylglucosamine (UDP-GlcNAc) in ammonia's inhibition of NCAM polysialylation was examined by adding glucosamine (GlcN) and uridine (Urd) to the cultures. This bypassed feedback inhibition of GlcN-6-P synthase and increased UDP-GlcNAc content by 25-fold in SCLC cells. After 3 days, PolySia levels were reduced to 10% of control with little effect on NCAM protein content. The extensive decrease in PolySia was confirmed in CHO cells. The effects of GlcN or Urd alone were less extensive, lending support to a specific role for UDP-GlcNAc in inhibition by ammonia. By comparison, 20 mM NH4Cl decreased PolySia content by 45% and increased UDP-GlcNAc in SCLC cells by 2-fold. The discrepancy between the ¿GlcN+Urd¿ and NH4Cl effects on UDP-GlcNAc and PolySia suggests that accumulation of UDP-GlcNAc is only partially responsible for decreased polysialylation in response to NH4Cl. In an attempt to increase NCAM polysialylation, N-acetylmannosamine and cytidine were added to cultures in order to circumvent the feedback inhibition of CMP-sialic acid synthesis. However, this only slightly increased PolySia levels and failed to counter ammonia's inhibition of NCAM polysialylation.

The lipofuscin content of Scarpas ganglion of normal and Menière's disease patients related to age: a histologic and morphometric study.

Vestibular ganglia were removed post mortem from 25 patients with normal inner ear function and 9 patients with known Menière's disease. The lipofuscin content of the ganglion cells of all specimens were analysed and the two groups compared. The age range of the non-Menière's patients was from 14 to 82 years, and of the Menière's patients from 42 to 72 years. All ganglion cells contained lipofuscin, mostly in the form of large granules. Lipofuscin was concentrated in the lateral areas of the ganglion cells and in each polar extension. In both groups the content of lipofuscin in ganglia increased with age. The increase in the Menière cases was greater. In age-matched data no non-Menière's ganglion reached the content of lipofuscin of a Menière's ganglion. The average percentage of lipofuscin in Scarpa's ganglion was determined by counting lipofuscin granule area in different levels of one ganglion. The portion of lipofuscin in the cytoplasm of ganglion cells of the Menière ganglions was increased about 44% compared with the non-Menière ganglions, if the average percentage of lipofuscin was set at 100%. The increase of 44% is nearly constant between 40 and 70 years. This is a relative increase, because the ganglion cells of the Menière's patients are 12% smaller than those of the healthy persons. Taking into account the different sizes of the ganglion cells these is an absolute increase of lipofuscin in the Menière cases of 28%.

[Evaluating the cost effectiveness of an ENT clinic by the physician. Development of a special cost and proceeds overview]. / Beurteilung der Wirtschaftlichkeit einer HNO-Klinik durch den Arzt. Entwicklung einer speziellen Kosten- und Erlösübersicht.

The realization of expense and proceeds-correctional measures in the area of medicine is a current problem caused by the lack of transparency of medical costs. The responsibility and the influence on management success is increasingly assigned on the head physicians. The concerning people should be informed about the economic status of their clinic. Only on this precondition selective and efficient measures are possible. Within the scope of a project in three different ENT-clinics, a special system of expense and proceeds-survey was developed using the existing cost accounting of the hospital. This survey enables the physician to estimate the economic efficiency and weakness of his clinic. After providing four auxiliary tables, it is possible to get a global view on the expenses and proceeds which are relevant for the physician. This method will allow to find the reasons for low rentability using different options of calculation. Systematic control of medical-economic processes will be considerably simplified for the physicians.

Blindness following paranasal sinus surgery: a report of two cases.

Two cases of blindness following paranasal sinus surgery are presented. The first patient, a 38-year old man, developed a delayed massive haemorrhage, after bilateral sphenoethmoidectomy. This hemorrhage could be stopped by electric cauterisation under endoscopical control. During this reintervention the patient developed total blindness of his right eye, and a restriction of the inferotemporal left visual field. The second patient, a 10-year old girl, developed, after bilateral spheno-ethmoidectomy for isolated sphenoiditis, total blindness of the left eye and paralysis of the ipsilateral extraocular muscles. According to the literature, blindness secondary to paranasal surgery is mainly due to retrobulbar hemorrhage. In the first case blindness was due to a direct cauterisation of the optic nerve, after perforation of the lamina papyracea. In the second case, blindness was probably due to a hemorrhage in the orbital apex.

A critical evaluation of the evidence on a causal relationship between Helicobacter pylori and otitis media with effusion.

OBJECTIVE: There is growing interest in the presence of Helicobacter pylori in the upper aerodigestive tract, and in the middle ear in patients with otitis media with effusion. Some studies have reported detecting H pylori in the middle ear, although reports to the contrary exist. In this study, we critically evaluate the evidence for the theory that H pylori in the middle ear plays a role in otitis media with effusion. MATERIAL: We undertook a systematic review of all available studies investigating the presence of H pylori in the middle ear of patients with otitis media with effusion. The current literature was critically analysed using the key words and phrases 'Helicobacter pylori' 'otitis media with effusion', 'serous otitis media', 'glue ear' and 'middle ear'. Six original research papers were identified, studying a total of 203 patients and 27 controls; two of these papers were randomised, controlled studies and four were prospective, cohort studies. RESULTS: At present, there is poor evidence for the existence of H pylori-associated otitis media with effusion. CONCLUSIONS: Further research in the field is needed in order to delineate the presence of H pylori and its role in the pathogenesis of otitis media with effusion.

[Uncertainties in preliminary calculations of overall treatment costs with special reference to costs of medical risk]. / Unklarheiten bei den Musterberechnungen der Fallpauschalen unter besonderer Berücksichtigung medizinischer Wagniskosten.

This paper explains the problems in calculating global compensation for medical treatment from the physician's point of view. This new system of financing hospitals will be introduced in Germany in 1996. In routine procedures such as tonsillectomy, the costs for complications are not sufficiently included in the price calculation. Basing on "postoperative bleeding after tonsillectomy" as an example, we calculated the costs of this complication per year. A scheme for calculating these costs as well as the costs for concomitant diseases for each case is presented. Evidently the overall price does not include substantial costs, and hence foreseeable losses are inevitable.

[Postoperative treatment after ear surgery]. / Nachbehandlung nach Ohroperationen.

The paper gives an overview on postoperative treatment after ear surgery, especially tympanoplastic, mastoid-surgery and stapes-surgery. Suggestions for treatment are given according to the different post-operative stages and situations. Careful cleaning of the ear canal, using the operative microscope, removal of debris, granulations and polyp and drying of the canal are most important.

[Postoperative complications in stapes surgery. An analysis of medical and economic aspects]. / Postoperative Komplikationen der Stapesplastik. Eine Analyse unter medizinisch-ökonomischen Aspekten.

With the establishment of DRGs in the German hospital financing system, knowledge of therapy costs and the suitability of therapies for reservation planning and medical cost management becomes important. Stapes surgery and its postoperative treatment is relatively standardised. The timing of intervention can be planned and serious complications are rare. We carried out a retrospective evaluation of all stapedectomies performed in Bochum University ENT department over 1 year ( n=46). The course of treatment and differences in expenditure between standard and complicated cases were recorded. We used the official calculation model of the Deutsche Krankenhausgesellschaft and the homogeneneity of the investigated patient groups was evaluated statistically. A total of 6.52% of all patients had complications, mainly temporary inner ear hearing deficit and vertigo, resulting in additional therapy. The average cost of a stapedectomy was 964 EUR for regular cases. The costs if complications occurred ranged from 1,754 EUR to 3,504 EUR. Statistical evaluation showed a strong homogeneity in the group of patients without complications, especially for the costs of surgery. Stapedectomy is suitable for flat rates due to the standardisation of therapy and the homogeneity of the patients. The profitability depends on the future DRG-flat-rate. Stapedectomy surgery seems to be appropriate for resource and cost management. To avoid unfair future losses for the hospitals, a mechanism of compensation for very expensive medical complications should be developed.

[Therapy of Frey's syndrome with an anhidrotic gel]. / Zur Therapie des Freyschen Syndroms durch ein Anhidrotisches Gel.

In recent years we treated 53 patients suffering from Frey's syndrome with an antihidrotic gel. The active ingredient we used was aluminiumtrichloridhexahydrate. In addition to presenting a historic review we will also demonstrate and discuss our results. The study concludes, that this gel is effective in treating Frey's syndrome.

Local anesthesia of the head and neck.

In theory, most ear, nose, and throat surgery involving the soft tissues of the head and neck may be performed under local anesthesia. This includes surgery on the middle ear, even mastoidectomy; partial or total laryngectomies; surgery on the nose and paranasal sinuses; and surgery on the major salivary glands. For this purpose, local anesthetics, with or without epinephrine, are administered either by infiltration injection or by topical application. The selection of either local or general anesthesia for a surgical procedure will depend on many important factors, not the least of which is the preference of the patient. This paper presents factors to be considered in making this choice, as well as surgical indications and contraindications to the use of local anesthesia.

[Abnormal postoperative findings in the external ear canal and tympanic membrane and their treatment]. / Abnorme postoperative Befunde im äusseren Gehörgang und am Trommelfell sowie deren Behandlung.

We describe uncommon complications after tympanoplasty affecting the outer auditory canal and the tympanic membrane such as stenosis of the auditory canal, fistulas, lateralization of the tympanic membrane, anulus cholesteatoma and cholesteatoma of the auditory canal. Typical findings are discussed and explained with the aid of illustrations. Treatment and indications for revision are discussed.

Considerations for osmolality measurement under elevated pCO(2): comparison of vapor pressure and freezing point osmometry.

Osmolality increases with pCO(2) in bioreactors with pH control, and it has been shown that osmolality compensation by decreasing the basal NaCl concentration partially mitigates the adverse effects of elevated pCO(2) on animal cell growth, protein production, and glycosylation. Thus, measurement of osmolality is important for a complete characterization of the culture environment under elevated pCO(2). However, osmolality measurement may be compromised by CO(2) evolution. Freezing point depression and vapor pressure depression osmometry were directly compared for the measurement of osmolality in samples at elevated pCO(2) (up to 250 mmHg) and at a variety of pH values (6.7-7.5). More extensive degassing may be expected with the vapor pressure osmometer due to the smaller sample volume and larger surface area employed. However, both types of osmometer yielded similar results for all pCO(2) and pH values studied. Moreover, the measured values agreed with osmolality values calculated using a semi-empirical model. Further analysis showed that, while sample degassing may result in a large decrease in pCO(2), there is little associated decrease in osmolality. The great majority of total CO(2) in solution is present as bicarbonate (HCO(3)(-)). Although a small amount of HCO(3)(-) is converted to CO(2) to compensate for CO(2) evolution, further depletion of HCO(3)(-) is inhibited by the associated increase in medium pH and by the need for HCO(3)(-) to maintain charge neutrality in solution. This explanation is consistent with the observed similarity in osmolality values for the two types of osmometer. It was also observed that osmolality did not change in samples that were frozen at -20 degrees C for up to 1 year.

An auto-continuous positive airway pressure device controlled exclusively by the forced oscillation technique.

The forced oscillation technique (FOT) has been demonstrated to be a very sensitive tool for the assessment of upper airway obstruction during nasal continuous positive airway pressure (CPAP) therapy for obstructive sleep apnoea (OSA). The present study was designed to evaluate the therapeutic efficacy of a novel auto-CPAP device based exclusively on the FOT. Following manual CPAP titration, 18 patients with OSA (mean apnoea/hypopnoea index (AHI) 48.0+/-28.1) were allocated to conventional CPAP and auto-CPAP treatment under polysomnographic control in randomized order. The patients were asked to assess their subjective daytime sleepiness using the Epworth Sleepiness Scale (ESS). The mean AHI during auto-CPAP treatment was 3.4+/-3.4 and was comparable with that obtained during conventional CPAP treatment (4.2+/-3.6). The analysis of sleep architecture, the arousal index (6.6+/-2.1 versus 7.3+/-4.4) or the ESS (5.6+/-1.8 versus 7.3+/-4.4) did not reveal any significant differences. However, the mean CPAP pressure during auto-CPAP treatment (0.84+/-0.26 kPa) and in particular the pressure applied in the lateral body position (0.74+/-0.35 kPa), was significantly lower than that employed in conventional CPAP treatment (0.93+/-0.16 kPa, both comparisons: p<0.05). The auto-continuous positive airway pressure device proved equally as effective as conventional continuous positive airway pressure. However, the mean treatment pressure was significantly reduced, especially when patients were sleeping in the lateral position.

Bicarbonate concentration and osmolality are key determinants in the inhibition of CHO cell polysialylation under elevated pCO(2) or pH.

Accumulation of CO(2) in animal cell cultures can be a significant problem during scale-up and production of recombinant glycoprotein biopharmaceuticals. By examining the cell-surface polysialic acid (PSA) content, we show that elevated CO(2) partial pressure (pCO(2)) can alter protein glycosylation. PSA is a high-molecular-weight polymer attached to several complex N-linked oligosaccharides on the neural cell adhesion molecule (NCAM), so that small changes in either core glycosylation or in polysialylation are amplified and easily measured. Flow-cytometric analysis revealed that PSA levels on Chinese hamster ovary (CHO) cells decrease with increasing pCO(2) in a dose-dependent manner, independent of any change in NCAM content. The results are highly pH-dependent, with a greater decrease in PSA at higher pH. By manipulating medium pH and pCO(2), we showed that decreases in PSA correlate well with bicarbonate concentration ([HCO(3)(-)]). In fact, it was possible to offset a 60% decrease in PSA content at 120 mm Hg pCO(2) by decreasing the pH from 7.3 to 6.9, such that [HCO(3)(-)] was lowered to that of control (38 mm Hg pCO(2)). When the increase in osmolality associated with elevated [HCO(3)(-)] was offset by decreasing the basal medium [NaCl], elevated [HCO(3)(-)] still caused a decrease in PSA, although less extensive than without osmolality control. By increasing [NaCl], we show that hyperosmolality alone decreases PSA content, but to a lesser extent than for the same osmolality increase due to elevated [NaHCO(3)]. In conclusion, we demonstrate the importance of pH and pCO(2) interactions, and show that [HCO(3)(-)] and osmolality can account for the observed changes in PSA content over a wide range of pH and pCO(2) values.

The JEVIN trial: a population-based survey on the quality of diabetes care in Germany: 1994/1995 compared to 1989/1990.

Since 1990 in most Eastern European countries health care systems have been decentralized or are undergoing the processes of decentralization. Increasingly, diabetic patients are no longer treated by diabetologists but by non-specialized physicians. During the same period structured treatment and teaching programmes have been introduced and health care is increasingly influenced by the St. Vincent declaration. To show the effect of these changes on the quality of diabetes care 90% (n = 244) of all insulin-treated diabetic patients aged 16 to 60 years and living in the city of Jena (100247 inhabitants) were studied in 1994/1995. The results were compared with the baseline examination of 1989/1990 (n = 190). HbA1c (HbA1c/mean normal) in IDDM patients under specialized care was similar in 1994/1995 (1.54 +/- 0.27, n = 47) to 1989/1990 (1.52 +/- 0.31, n = 131, p = 0.0018), but higher under non-specialized care (1.71 +/- 0.38, n = 80, p = 0.0087). In the total group of NIDDM patients there was no significant change in HbA1c (1994/1995: 1.75 +/- 0.4, n = 117, vs 1989/1990: 1.78 +/- 0.4, n = 59, p = 0.67), but with a tendency to higher HbA1c under non-specialized (1.81 +/- 0.4, n = 79) compared to specialized care (1.66 +/- 0.39, n = 38, p = 0.06). Incidence of severe hypoglycaemia (IDDM 0.13; NIDDM 0.04), ketoacidosis (0.02; 0.01) and the prevalence of nephropathy (21%; 35%) and neuropathy (24%; 38%) remained unchanged in comparison to 1989/1990, whereas there was an increase in the prevalence of diabetic retinopathy. Specialized care is mandatory for patients with IDDM.

Sensitivity of a simplified forced oscillation technique for detection of upper airway obstruction.

The sensitivity of a simplified variant of forced oscillation technique (FOT) was studied for assessment of dynamic upper airway obstruction during nasal continuous positive airway pressure (nCPAP) therapy for obstructive sleep apnoea (OSA). The airway impedance P[FOT] was measured by FOT and the oesophageal pressure (P(oes)) was recorded during stable stage II sleep in 11 patients with OSA. The CPAP level was initially set high enough to completely abolish upper airway obstruction. To induce gradually increasing upper airway re-obstruction, the CPAP pressure was then lowered stepwise. Thirty six such manoeuvres were analysed, blind, to define the first inspiration at which upper airway re-obstruction was detectable by analysis of P[FOT](t(FOT)) and by P(oes)(t(oes)), respectively. On seven occasions t(FOT) and t(oes) occurred together, in the remaining 29 cases t(FOT) preceded t(oes) with a mean latency of 6.0+/-7.7 (0-32) breath cycles. In no case did t(oes) preceed t(FOT). FOT is a highly sensitive tool for the assessment of incipient upper airway obstruction during nCPAP therapy.