Correction to: Safety and efficacy of Cerebrolysin in acute brain injury and neurorecovery: CAPTAIN I-a randomized, placebo-controlled, double-blind, Asian-Pacific trial.

The above article was published online with incorrect abbreviations in Figures 2 and 3 last sentence of the legend. HDA should be corrected to HADS.

Safety and efficacy of Cerebrolysin in acute brain injury and neurorecovery: CAPTAIN I-a randomized, placebo-controlled, double-blind, Asian-Pacific trial.

OBJECTIVE: To evaluate the safety and efficacy of Cerebrolysin as an add-on therapy to local standard treatment protocol in patients after moderate-to-severe traumatic brain injury. METHODS: The patients received the study medication in addition to standard care (50 mL of Cerebrolysin or physiological saline solution daily for 10 days, followed by two additional treatment cycles with 10 mL daily for 10 days) in a prospective, randomized, double-blind, placebo-controlled, parallel-group, multi-centre phase IIIb/IV trial. The primary endpoint was a multidimensional ensemble of 14 outcome scales pooled to be analyzed by means of the multivariate, correlation-sensitive Wei-Lachin procedure. RESULTS: In 46 enrolled TBI patients (Cerebrolysin 22, placebo 24), three single outcomes showed stand-alone statistically significant superiority of Cerebrolysin [Stroop Word/Dots Interference (p = 0.0415, Mann-Whitney(MW) = 0.6816, 95% CI 0.51-0.86); Color Trails Tests 1 and 2 (p = 0.0223/0.0170, MW = 0.72/0.73, 95% CI 0.53-0.90/0.54-0.91), both effect sizes lying above the benchmark for "large" superiority (MW > 0.71)]. While for the primary multivariate ensemble, statistical significance was just missed in the intention-to-treat population (pWei-Lachin < 0.1, MWcombined = 0.63, 95% CI 0.48-0.77, derived standardized mean difference (SMD) 0.45, 95% CI -0.07 to 1.04, derived OR 2.1, 95% CI 0.89-5.95), the per-protocol analysis showed a statistical significant superiority of Cerebrolysin (pWei-Lachin = 0.0240, MWcombined = 0.69, 95% CI 0.53 to 0.85, derived SMD 0.69, 95% CI 0.09 to 1.47, derived OR 3.2, 95% CI 1.16 to 12.8), with effect sizes of six single outcomes lying above the benchmark for "large" superiority. Safety aspects were comparable to placebo. CONCLUSION: Our trial suggests beneficial effects of Cerebrolysin on outcome after TBI. Results should be confirmed by a larger RCT with a comparable multidimensional approach.

Studies toward the comprehension of fungal-macroalgae interaction in cold marine regions from a biotechnological perspective.

In marine ecosystems, macroalgae are the habitat for several microorganisms, fungi being among them. In the Antarctic benthic coastal ecosystem, macroalgae play a key role in organic matter cycling. In this study, 13 different macroalgae from Potter Cove and surrounding areas were sampled and 48 fungal isolates were obtained from six species, four Rhodophyta Ballia callitricha, Gigartina skottsbergii, Neuroglossum delesseriae and Palmaria decipiens, and two Phaeophyceae: Adenocystis utricularis and Ascoseira mirabilis. Fungal isolates mostly belonged to the Ascomycota phylum (Antarctomyces, Cadophora, Cladosporium, Penicillium, Phialocephala, and Pseudogymnoascus) and only one to the phylum Mucoromycota. Two of the isolates could not be identified to genus level, implying that Antarctica is a source of probable novel fungal taxa with enormous bioprospecting and biotechnological potential. 73% of the fungal isolates were moderate eurypsychrophilic (they grew at 5-25 °C), 12.5% were eurypsychrophilic and grew in the whole range, 12.5% of the isolates were narrow eurypsychrophilic (growth at 15-25 °C), and Mucoromycota AUe4 was classified as stenopsychrophilic as it grew at 5-15 °C. Organic extracts of seven macroalgae from which no fungal growth was obtained (three red algae Georgiella confluens, Gymnogongrus turquetii, Plocamium cartlagineum, and four brown algae Desmarestia anceps, D. Antarctica, Desmarestia menziesii, Himantothallus grandifolius) were tested against representative fungi of the genera isolated in this work. All extracts presented fungal inhibition, those from Plocamium cartilagineum and G. turquetii showed the best results, and for most of these macroalgae, this represents the first report of antifungal activity and constitute a promising source of compounds for future evaluation.

The microvascular network of the pituitary gland: a model for the application of fractal geometry to the analysis of angioarchitecture and angiogenesis of brain tumors.

In geometrical terms, tumor vascularity is an exemplary anatomical system that irregularly fills a three-dimensional Euclidean space. This physical characteristic, together with the highly variable vessel shapes and surfaces, leads to considerable spatial and temporal heterogeneity in the delivery of oxygen, nutrients and drugs, and the removal of metabolites. Although these biological features have now been well established, quantitative analyses of neovascularity in two-dimensional histological sections still fail to view tumor architecture in non-Euclidean terms, and this leads to errors in visually interpreting the same tumor, and discordant results from different laboratories. A review of the literature concerning the application of microvessel density (MVD) estimates, an Euclidean-based approach used to quantify vascularity in normal and neoplastic pituitary tissues, revealed some disagreements in the results and led us to discuss the limitations of the Euclidean quantification of vascularity. Consequently, we introduced fractal geometry as a better means of quantifying the microvasculature of normal pituitary glands and pituitary adenomas, and found that the use of the surface fractal dimension is more appropriate than MVD for analysing the vascular network of both. We propose extending the application of this model to the analysis of the angiogenesis and angioarchitecture of brain tumors.

Growth hormone-prolactin-thyrotropin-secreting pituitary adenoma in atypical McCune-Albright syndrome with functionally normal Gs alpha protein.

The McCune-Albright syndrome (MAS) comprises a triad of physical signs: localized bone lesions termed polyostotic fibrous dysplasia, café-au-lait pigmentation of the skin, and autonomous hyperfunction of multiple endocrine systems, including overproduction of GH and T4. A somatic activating point mutation in the gene for the alpha-subunit of the G-protein (Gs alpha) in the affected tissue has been claimed to be the underlying defect. A 29-yr-old patient with MAS, showing polyostotic fibrous dysplasia associated with acromegalic features, underwent endocrinological studies, including oral glucose tolerance test and pituitary stimulation test, and magnetic resonance imaging, revealing elevated plasma concentrations of GH, PRL, and secondary hyperthyroidism due to pituitary macroadenoma infiltrating the sphenoid cavity and extending to the suprasellar space. Subsequently, reduction of tumor mass by a transsphenoidal and a subsequent subfrontal operation led to only marginal amelioration of the excessive hormone production. Postsurgery octreotide and bromocriptine therapy induced near-normalization of hormone concentrations. Immunohistochemistry of tumor tissue confirmed the plurihormonal character, but DNA sequence analysis did not detect any of the two known activating mutations in the Gs alpha gene. Furthermore, biochemical tests revealed normal Gs alpha function, ruling out other mutations that lead to constitutive Gs alpha activation. Our study documents that MAS is a heterogeneous disease. Some, but clearly not all, patients have oncogenic mutations of the gene coding for Gs alpha. Any gene acting down-stream of Gs can theoretically be predicted to result in the same phenotype. In addition, hyperthyroidism of MAS may be secondary to a TSH-producing pituitary macroadenoma.

Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings.

We present 25 pituitary adenomas that were confirmed surgically to have invaded the cavernous sinus space. The surgical results are compared with the preoperative magnetic resonance imaging findings. For comparable radiological criteria, we classified parasellar growth into five grades. This proposed classification is based on coronal sections of unenhanced and gadolinium diethylene-triamine-pentaacetic acid enhanced magnetic resonance imaging scans, with the readily detectable internal carotid artery serving as the radiological landmark. The anatomical, radiological, and surgical conditions of each grade are considered. Grades 0, 1, 2, and 3 are distinguished from each other by a medial tangent, the intercarotid line--through the cross-sectional centers--and a lateral tangent on the intra- and supracavernous internal carotid arteries. Grade 0 represents the normal condition, and Grade 4 corresponds to the total encasement of the intracavernous carotid artery. According to this classification, surgically proven invasion of the cavernous sinus space was present in all Grade 4 and Grade 3 cases and in all but one of the Grade 2 cases; no invasion was present in Grade 0 and Grade 1 cases. Therefore, the critical area where invasion of the cavernous sinus space becomes very likely and can be proven surgically is located between the intercarotid line and the lateral tangent, which is represented by our Grade 2. We also measured tumor growth rates, using the monoclonal antibody KI-67, which shows a statistically higher proliferation rate (P < 0.001) in adenomas with surgically observed invasion into the cavernous sinus space, as compared with noninvasive adenomas.

Meningiomas of the space of the cavernous sinus.

During the years 1985 to 1992, we encountered 59 patients with meningiomas involving the space of the cavernous sinus. In 29 of these patients, meningiomas were primarily located within the space of the cavernous sinus and were operated on without mortality and with low morbidity. A small subtemporal surgical approach was favored, which allowed initial tumor resection from the posterior aspect, where the Parkinson's triangle is wide, thus avoiding the additional morbidity of large-scale approaches. According to the relationships of the all-important cranial nerves passing within the lateral wall of the cavernous sinus, we divided the primary intracavernous meningiomas into four types, which reflected not only the preoperative cranial nerve deficit but also the feasibility of surgical resection. Cranial nerve function deteriorated after operations in 14% of oculomotor nerves, in one abducent nerve, in 58% of trochlear nerves, and in 21% of trigeminal nerves. We encountered improvement of function in 43% of oculomotor nerves, in 50% of abducent nerves, and in approximately 30% of the second and third but in only 7% of the first branches of trigeminal nerves. There was no improvement in trochlear nerve function. Improvement of oculomotor nerve function was observed only in moderately impaired nerves, which indicates that surgery should be undertaken early to preserve or improve oculomotor nerve function.

Neurotopographic considerations in the microsurgical treatment of small acoustic neurinomas.

OBJECT: The authors studied the relationships between tumor size, location, and topographic position relative to the intact facial nerve bundles in acoustic neurinomas to determine the influence of these factors on hearing preservation postoperatively. Consistent topographic relationships were found. METHODS: Four hundred fifty-two patients with acoustic neurinoma treated via a retrosigmoid approach were analyzed with respect to hearing preservation and facial nerve function. One hundred fifteen tumors were identified as small and were categorized as Grades I and II. Patients with Grade I tumors, that is, purely intracanalicular lesions, all had good hearing preoperatively, defined by a less than 50-dB pure tone average and 50% speech discrimination score. All 14 Grade I tumors were removed, resulting in preservation of the patient's hearing by these criteria. There were no particular topographic anatomical relationships associated with these tumors that affected hearing preservation. Grade II tumors, defined as those protruding into the cerebellopontine angle without contacting the brainstem, were found in 101 patients and were divided by size into two grades: IIA (< 1 cm) and IIB (1-1.8 cm). In 90 patients with Grade IIA tumors, 72 (89%) of 81 who had preserved hearing preoperatively maintained it postoperatively, and in the 11 patients with Grade IIB tumors, six of whom had good hearing preoperatively, four (67%) had preserved hearing postoperatively. Six morphological types were identified based on their neurotopographic relationships to the elements of the vestibulocochlear nerve. CONCLUSIONS: Hearing preservation postsurgery by tumor type was as follows: 1A, 92%; 1B, 88%; 1C, 100%; 2A, 83%; 2B, 92%; and 3, 57%. Combined, this represents a hearing preservation rate of 87% after surgical treatment of Grade II acoustic neurinomas. Full nerve function was maintained in 88% of patients with anatomically preserved facial nerves in both Grade I and II tumors. The remaining 12% of patients retained partial function of the facial nerve. Two patients in the series lost anatomical integrity of the nerve due to surgery.

Detection of tumor necrosis factor-alpha protein and messenger RNA in human glial brain tumors: comparison of immunohistochemistry with in situ hybridization using molecular probes.

Tumor necrosis factor-alpha (TNF alpha) protein and messenger (m)RNA distribution was studied in biopsy samples of glial brain tumors, using immunohistochemistry and in situ hybridization with molecular probes, to investigate the role of this cytokine in tumor proliferation and immunological host defense. Focal expression of TNF alpha was detected in four of four glioblastomas, one of two anaplastic astrocytomas, and four of five low-grade astrocytomas, regardless of their subtype or grade of malignancy, but in none of the normal peritumoral brain tissues used as controls. The TNF alpha protein and mRNA were present in reactive astrocytes and protoplasmic tumor cells, confined to areas of leukocyte or T-lymphocyte infiltrating, and less pronounced in tumor cells at the edge of necrosis. Additionally, TNF alpha reactivity was found in infiltrating macrophages and perivascular microglia. Immunohistochemistry and in situ hybridization for TNF alpha showed comparable reaction patterns and numbers of TNF alpha-positive cells, even though the sensitivity of in situ hybridization was significantly higher. Quantitative evaluation of TNF alpha protein, TNF alpha mRNA, and leukocyte infiltration revealed a significant positive correlation between the TNF alpha-positive reactive astrocytes and the number of lymphocytes present in corresponding areas. Together, these data lead to the conclusion that TNF alpha in reactive astrocytes and monocytic cells within tumor areas of high leukocyte infiltration and in tumor cells at the border of necrosis may represent one defense pathway of the immune system against tumor proliferation.

Hemostasis activation in patients undergoing brain tumor surgery.

Patients undergoing brain tumor surgery are at high risk for the occurrence of a thromboembolic event. To identify a laboratory marker suitable for risk estimation the authors studied the perioperative time pattern of routine coagulation parameters and the specific hemostasis activation marker D-dimer in 28 consecutive patients at high risk (11 patients with glioma and eight patients with meningioma) and low risk (nine patients with metastases) for thromboembolism, as previously reported. As is typical during major surgery, most of the routine parameters declined, probably because of hemodilution, and recovered postoperatively to values higher than baseline, probably because of an acute-phase reaction. On Days 2 and 7 after surgery no difference in the routine parameters was recorded between patients at high (meningioma and glioma) and low risk (metastasis). The level of D-dimer was elevated at baseline in patients with metastasis, indicating a hemostatic hyperactivity that is usual in cancer patients. During surgery a marked increase in D-dimer levels occurred in patients with meningioma and glioma (pre- and postoperative median 90/2000 and 100/1020 ng/ml, respectively), but the increase was less pronounced in patients with metastasis (320/660 ng/ml). Postoperatively, D-dimer declined in patients with metastases to lower than preoperative levels (Day 7, 270 ng/ml); in patients with meningioma or glioma, however, D-dimer levels remained elevated until Day 7 (450 and 200 ng/ml, respectively). These results indicate that levels of D-dimer correlate with the reported high risk for thromboembolism in patients with meningioma and glioma, and D-dimer should be evaluated for its use in estimating individual risk and the efficiency of its use in the control of prophylactic treatment.

[Noninvasive follow-up by color-coded Doppler sonography after surgical interventions on the extracranial cerebral arteries]. / Nicht-invasive Verlaufskontrolle mittels farbkodierter Doppler-Sonographie nach operativen Eingriffen an den extrakraniellen hirnversorgenden Arterien.

By means of colour-coded Doppler sonography we studied retrospectively the incidence of postoperative changes in 54 patients following 58 carotid endarterectomies. The interval between operation and ultrasound varied from one to 41 months. The overall incidence of recurrent carotid disease was 50% with a 31% (18 of 58) of hemodynamically insignificant restenoses, a 13.8% (8 of 58) incidence of haemodynamically significant restenoses, and a 5.2% (3 of 58) of occlusions. The segment that had been endarterectomized showed a bulbous dilatation in 24.1% (14 of 58). In all of these cases extensive flow reversal zones could be demonstrated, the possible importance of which is discussed. Examinations in 9 patients with reimplantation of subclavian artery to the common carotid artery and grafting technique between these arteries and in 11 patients with reimplantation of vertebral artery to the common carotid artery demonstrated one occlusion of the ipsilateral vertebral artery.

An unusual management of an open compound depressed skull fracture with venous sinus involvement. A case report.

A neurosurgical management of an open compound depressed fracture perforating the superior sagittal sinus is reported. Undue bleeding from the fracture did not allow a conservative management. The patient had been operated primarily at an outside emergency surgery unit. Profuse uncontrollable bleeding made a tamponade of the sinus necessary for transportation to our neurosurgical department. After reconstruction of the sinus he survived without evidence of a neurological deficit.

Another case of acoustic schwannoma and epidermoid cyst occurring as a single cerebellopontine angle mass: possibly not so rare?

This is the second case of adjacent occurrence of an acoustic schwannoma and epidermoid cyst in the cerebellopontine angle. This case of a 70-year-old woman is presented with a history of her illness, neuroradiologic data, and photographs during the operation. We compare this case with the first of its kind.

The course of the prevertebral segment of the vertebral artery: anatomy and clinical significance.

BACKGROUND: The so called "pretransverse or prevertebral segment" of the vertebral artery is defined from its origin at the subclavian artery to its entry into the respective transverse foramen. In surgery, angiography, and in all noninvasive procedures it is of great importance to know the exact details of the course and the origin of this segment of the vessel as well as in which percentages real abnormalities can be found. METHODS: The VI segment of the vertebral artery was investigated both in anatomic preparations and clinical studies. A total of 402 vertebral arteries were evaluated (70 anatomic preparations in different forms, 181 patients, 95 angiographies of the aortic arch, and 86 color coded doppler sonographies). RESULTS: A contorted course was found in 157 (39%) cases. The plane of tortuosities demonstrated by the respective vessels was found to be horizontal in 40 (44.9%) cases, sagittal in 30 (33.7%) cases, and frontal in 19 (21.4%) cases. In 51 (32.5%) cases the contorted pathway was on the right side, and in 106 (68%) cases, on the left. A hypoplasia was found in 16 (10%) cases--11 (4.8%) right and 5 (2.2%) left. We further differentiated the convexity lying either medially or laterally in the transverse or frontal plane, or oriented dorsally or ventral in the sagittal plane. The exact location of the origin of the artery on the circumference of the subclavian artery (47% cranial, 44% dorsal, 3% ventral, 6% caudal) and also the average values of length and diameter are described. No significant differences between tortuous and nontortuous vessels were found with respect to length and diameter. A real abnormality of the origin of the vertebral artery was found in 8 (3.5%) cases. CONCLUSIONS: The described morphologic variations and frequencies of the VI segment of the vertebral artery have clinical applications in a wide field of pathologies in that region. To know about these findings seems to be very important not only in diagnosis (angiography, color coded doppler sonography) but also in their surgical and endovascular treatment.

Frameless stereotactic lesion contour-guided surgery using a computer-navigated microscope.

BACKGROUND: The Zeiss MKM System is a recently developed computerized operating microscope for image-guided neurosurgery. The clinical advantages, reliability, accuracy, and limitations of this technique were investigated. METHODS: Since February 1995, 78 consecutive frameless stereotactic image-guided procedures were performed in 73 patients (30 males, 43 females; mean age, 46.9 years; range, 16-77 years) for tumor surgery (50/64.1%), cavernoma removal (16/20.5%), and functional procedures (12/15.4%). Skin markers (74 cases) or bone markers (4 cases) and a standard imaging protocol (2-mm cranial computed tomography (CCT) in 59 cases/1.5-mm magnetic resonance imaging (MRI) in 19 cases) were used. RESULTS: The main advantages were pre-operative skin incision, craniotomy and corticotomy planning, and determination of lesion boundaries. Useful registration and system reliability were noted in 97% (76/78) of the procedures. A significant improvement in registration accuracy was observed over the test period from a mean of 4.8 mm (SD = 3.36; Cases 1-25) to a mean of 2.2 mm (SD = 0.86; Cases 26-78). This resulted in an improvement in application accuracy from <5 mm in 71% (Cases 1-25) to <2 mm in 95% (Cases 26-78) of cases, and the accuracy led to successful localization of the lesion in every case. Accuracy was reliable at the beginning of every procedure, but degraded to values >5 mm by the end of the procedure in 29% (22/78) of cases. MRI cases achieved higher application accuracy values (2.1 mm mean) than CT cases (3.7 mm mean). CONCLUSIONS: The system offers a reliable alternative to frame-assisted stereotactic craniotomies in lesion targeting, but would need an intraoperative image update for resection guidance.

Neuroanatomical details under endoscopical view--relevant for radiosurgery?

Both, neuroendoscopy and radiosurgery, are upcoming techniques in neurosurgery and become nowadays more and more important. In planning radiosurgical interventions it is very important to have both, the information about the morphology of the pathology itself, and also a clear understanding from the surrounding structures. Neuroendoscopic techniques gives the possibility to demonstrate well known structures without prior dissection. This paper focuses on these anatomical informations which might be relevant in planning further radiosurgical interventions especially in cases of the vascularization of the cranial nerves and the arachnoid membranes, these structures appears much more complex than described in "common" neuroanatomical textbooks. Endoscopic techniques also better demonstrate the real in vivo relationships and gives so a better understanding for interpreting "planning" MRI and CT scans. We therefore consider that neuroanatomical studies under a neuroendoscopical view are very important and could be very helpful in planning radiosurgical intervensitons.

Intra-operative marking of neuroanatomical details--helpful for radiosurgery?

This report is a list of simple but effective techniques for marking important structures intra-operatively. During the last 2 years in 52 patients intra-operative marking techniques have been used. In 37 cases a small piece of fat has been taken. In 10 patients it was done by a radiopaque Barium impregnated silicon sphere and in 5 patients with a piece of a monofilament suture. Postoperative checks were done by conventional X-ray, computer tomography and Magnetic Resonance Imaging. The indication in all cases was to offer landmarks helpful for planning postoperative radiosurgery. In case of fat and radiopaque Barium impregnated silicone spheres the markings were always well defined and clear in contrast. In those cases where a piece of monofilament suture was used it was impossible to get clear postoperative information. In general there were no intra- or post-operative complications. All markers were well tolerated and no side effects have been observed so far. The advantages and disadvantages of each of these possibilities are described and discussed.

Microsurgery versus radiosurgery in the treatment of small acoustic neurinomas.

Microsurgical preservation of the facial nerve during removal of acoustic neurinomas can hardly be compared with microsurgery of the eighth cranial nerve. Many more anatomical and pathogenetic factors are involved that need careful consideration. In small neurinomas, of grades I and II, total extirpation of the tumour with preservation of both the facial nerve and segments of the vestibulocochlear nerve not directly involved by the tumour has become a safe and practical technique. In small acoustic neurinomas immediate facial nerve function could be preserved in 88% and "useful hearing" could be preserved in 78%. A number of different types of tumour-cranial nerve relationships could be established in small acoustic neurinomas, showing also the effects of adjusted surgical techniques on the preservation of hearing. Optimal selective separation of cranial nerves from the tumour is only possible through open surgical intervention, while radiosurgery requires the irradiation of the entire tumour/nerve complex.

Hemostasis activation in patients undergoing brain tumor surgery.

Patients undergoing brain tumor surgery are at high risk for the occurrence of a thromboembolic event. To identify a laboratory marker suitable for risk estimation the authors studied the perioperative time pattern of routine coagulation parameters and the specific hemostasis activation marker D-dimer in 28 consecutive patients at high risk (11 patients with glioma and eight patients with meningioma) and low risk ( 9 patients with metastases) for thromboembolism, as previously reported. As is typical during major surgery, most of the routine parameters declined, probably because of hemodilution, and recovered postoperatively to values higher than baseline, probably because of an acute-phase reaction. On Days 2 and 7 after surgery no difference in the routine parameters was recorded between patients at high (meningioma and glioma) and low risk (metastases). The level of D-dimer was elevated at baseline in patients with metastases, indicating a hemostatic hyperactivity that is usual in cancer patients. During surgery a marked increase in D-dimer levels occurred in patients with meningioma and glioma (pre- and postoperative median 90/2000 and 100/1020 ng/ml, respectively), but the increase was less pronounced in patients with metastases (320/660 ng/ml). Postoperatively, D-dimer declined in patients with metastases to lower levels than preoperatively (Day 7, 270 ng/ml); in patients with meningioma or glioma, however, D-dimer levels remained elevated until Day 7 (450 and 200 ng/ml). These results indicate that levels of D-dimer correlate with the reported high risk for thromboembolism in patients with meningioma and glioma, and D-dimer should be evaluated for its use in estimating individual risk and the efficiency of its use in the control of prophylactic treatment.

Salivary levels of gramicidin after use of a tyrothricin-containing gargle/mouth-wash and tyrothricin lozenges.

Three pharmaceutical preparations for the disinfection of the oropharynx were tested with regard to the gramicidin concentration obtained in the saliva after their appropriate application. Peak values followed a dose-concentration relationship and were highest after sucking a lozenge containing 10 mg tyrothricin (mean 109.3 mg/L) followed by that of a gargle/mouth-wash containing 667 mg tyrothricin/L (mean 21.1 mg/L) and of a lozenge containing 4 mg tyrothricin (mean 14.4 mg/L).