Superficial Muscle Layer Research Articles

Prototype 3‐D Model of the Musculotendinous Architecture of Infraspinatus

Muscle architecture, the arrangement of fibre bundles within the muscle volume, has important functional implications. Previous studies of infraspinatus (IS) muscle architecture have focused on dissection and photography of the superficial muscle layers rather than a volumetric analysis. The aim of this study was to develop a methodology to quantify the architectural parameters of the fibre bundles throughout the volume of IS. As a prototype, one formalin‐embalmed cadaveric specimen was used. The IS was exposed and each fibre bundle was meticulously dissected and digitized from end to end. The digitized data was imported and a 3D model of the fibre bundle architecture, as in situ, was constructed in Autodesk® Maya®2012. Architectural parameters including fibre bundle length (FBL), pennation angle (PA), and physiological cross sectional area (PCSA) were computed. Based on the architectural parameters, muscular partitioning was determined. This technique successfully captured IS architecture throughout its volume. The IS was found to consist of 2 architecturally distinct regions, superior and inferior. The average measures for the superior and inferior regions were respectively: FBL 115.3mm; PA 22.2°; PCSA 180.3mm2 and FBL 84.9 mm; PA 15.9°; PCSA 550.5 mm2. The results suggest that there is muscular partitioning of the IS. This methodology will form the basis of a continuing study to understand detailed IS architecture at the fibre bundle level.

Is there a difference in the pattern of muscle activity when performing neck exercises with a guild board versus a pulley?

Guild boards and pulleys are apparatus commonly used to train cervical muscle function for their purported benefit in facilitating activity of the deeper muscle layers, although this effect has not been substantiated. The objective of this study was to compare the activity of the different layers of cervical muscles when performing exercise with these 2 types of apparatus. A total of 19 healthy persons (mean age 28 years, (standard deviation 7 years). Ultrasound measurements of muscle deformation and deformation rate were recorded from the dorsal and ventral neck muscle layers during extension and flexion exercises. Pulley exercises were performed in the upright sitting position against a standardized resistance (men 2 kg, women 1 kg) and guild board exercises at an angle of 45º. The dorsal muscles generally showed greater levels of deformation and deformation rate during exercise with the guild board compared with the pulley system (p < 0.05), but with no significant differences in relative activity between the deep and superficial muscle layers (condition × muscle interaction (p > 0.05)). No differences were observed for the ventral muscles between exercise methods (p > 0.05). While both exercise methods appear to train cervical muscle function, neither appear to be more selective in facilitating deep cervical muscle activity, probably as they involve very similar cervical kinematics.

Immunohistochemical Staining for Smoothelin in the Duplicated Versus the True Muscularis Mucosae of Barrett Esophagus

The muscularis mucosa underlying the metaplastic mucosa of Barrett esophagus is frequently duplicated, with an intervening layer of lamina propria between the superficial or neomuscularis mucosa (NMM) and the deep/true muscularis mucosa (TMM). This duplication causes difficulties with accurate staging of superficially invasive carcinoma in biopsy specimens and endoscopic mucosal resections (EMRs), as invasion underneath the superficial muscle layers may be mistaken for submucosal invasion. Mucosal resections or other ablative nonsurgical therapies can be curative in patients with esophageal intramucosal carcinoma, whereas patients with submucosal invasion are recommended for esophagectomy. Therefore, the accurate staging of such specimens is crucial. Smoothelin is a novel smooth muscle protein expressed only by fully differentiated smooth muscle cells and not by proliferative or noncontractile smooth muscle cells and fibroblasts. It has been suggested that in the bladder, immunohistochemistry for smoothelin may help separate hyperplastic muscularis mucosa from the true muscularis propria. We hypothesized that in the esophagus, immunohistochemistry for smoothelin would differentiate the NMM from the TMM. Thirty cases of EMRs for Barrett esophagus-related neoplasia were retrieved from the archives of the pathology department, St Michael's Hospital. Immunohistochemical staining for smoothelin was performed to evaluate differential staining in the TMM versus NMM. Fifteen cases were stained for smooth muscle actin and smooth muscle myosin. The staining score was evaluated on a scale from 0 to 3 according to the percentage and intensity of staining. Immunohistochemical staining results for smoothelin were as follows: the NMM showed weak focal staining (+1) in 23 of 30 cases (82%), and moderate staining (+2) in 7 of 30 cases (12%), and the TMM showed very strong and diffuse staining (+3) in 30 of 30 cases. No cases showed negative (0) staining in the NMM. With smooth muscle actin and myosin, strong and diffuse staining was observed with similar intensity in both the TMM and NMM in 15 of 15 cases. In our study, smoothelin staining in the NMM is significantly weaker than that seen in the true/deep muscularis mucosa. This pattern is similar to that reported for the muscularis mucosae of the urinary bladder. Although smoothelin can readily distinguish the 2 layers, its value might be limited by the need to simultaneously compare the 2 layers. Although this might be of use in EMR specimens in which both layers are visible, use in biopsies may be limited as the residual staining in the NMM may inhibit definitive evaluation. This issue may be resolved by the use of appropriate standard controls, individual optimization of the antibody, and the use of an automated digital assessment.

Transurethral resection of the bladder tumour (TURBT) for non‐muscle invasive bladder cancer: Basic skills

Transurethral resection of the bladder tumour (TURBT) is the standard surgical procedure for non-muscle invasive bladder cancer. We believe that all urologists should be trained in this procedure. This DVD provides an overview of TURBT with particular focus on basic skills, including basic surgical techniques such as the obturator nerve block. Important basic surgical skills required for complete TURBT in non-muscle invasive bladder cancer are: (i) resection of all visible tumors; (ii) resection of apparently normal mucosa on the border of the tumor; (iii) resection of the muscle layer at the base of the tumor until normal muscle fibers are visible; (iv) in applicable cases, random biopsy of apparently normal urothelium of the bladder wall and transurethral resection (TUR) biopsy of both sides of the prostatic urethra; and (v) when possible, after these procedures are completed, a different operating surgeon should inspect the bladder lumen to confirm that there are no remaining tumors. In particular, sampling resection should be implemented in apparently normal mucosa for approximately 1 cm around the tumor, and at the base of the tumor down to the superficial muscle layer. Resected specimens should be examined histopathologically in order to confirm the absence of malignant findings. Fundamental procedures for TURBT include both one-stage and two-stage resection. One-stage resection is used for relatively small tumors and involves a single procedure with simultaneous resection of both the tumor and the tissue at the tumor base down to the superficial muscle layer. In the two-stage resection, the first resection exposes the lower level of the mucosa and the second resection removes that lower mucosal layer in order to sample the superficial muscle layer for cancer staging. At the start of the resection, the loop is electrified before it makes contact with the mucosa. Delicate movements of the sheath should be used, along with delicate movement of the loop itself to adjust the depth of resection. The illustration of surgical techniques shows not only the basic techniques but also some points for caution during the resection. For actual resection, it is important to fully understand the properties of the tumor and to combine these techniques appropriately for each individual resection procedure. When resecting multiple tumors, the same basic resection techniques used for single tumors should be applied, and repeated as necessary. (This is a translated section of a video article originally published in Japanese as a DVD in the Audio-Visual Journal Vol.14 No.1. 2008 by The Japanese Urological Association.).

Conflicting Finding on Intramucosal Colon Cancers Based on National Survival Outcomes Data

TO THE EDITOR: The article by Gunderson et al provides powerful evidence to support the revised staging system in the seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual for colon cancer. The case numbers of national-based survival data are large enough to explore significant subtle staging factors. However, an interesting point about Tis colon cancers is worthy of deeper discussion, which was not mentioned in the article. We found the contents both in Table 1 and Table 2 in this article showed that a proportion of Tis colon cancers had lymph node metastasis, with a very low incidence. A total of 5,939 patients had Tis colon cancer, and 95 patients (1.6%) had N1 disease and 19 patients (0.32%) had N2 disease. This finding challenges our previous general rule that colon cancer confined to the mucosa has no chance of metastasis and thus no further treatment is needed. According to the previous AJCC consensus in 2000, colon tumors invading the lamina propria up to and including the muscularis mucosae have no associated risk of regional lymph node metastasis. However, recent data using immunohistochemical marker D2-40 have shown the presence of lymphatic channels extending to the colonic mucosa in neoplastic and inflammatory conditions. Literature on the subject of metastatic risk in intramucosal colorectal carcinoma is extremely limited. Only one patient with poorly differentiated intramucosal rectal cancer had recurrence after surgical resection. We reviewed the patient group in our hospital. In total, there were 3,196 patients with colorectal cancer who received treatment at our hospital during 1999 to 2005. Among the 118 patients receiving regional resection for Tis tumors, no lymph node metastasis was found, except in one patient with a polypoid lesion. The pathology slides of this patient were reviewed carefully, and the tumor was actually a T2 lesion that invaded the superficial muscle layer. In fact, certain types of intramucosal cancer can have lymph node metastasis in gastric cancer. In colorectal cancer, data are still lacking regarding lymph node metastasis in intramucosal tumors. We suggest that all pathologic slides of these intramucosal colon cancers with lymph node metastasis in this article should be reviewed carefully, if possible, to certify the actual invasion depth of the tumor. If it is true that lymph node metastasis could occur in intramucosal colon cancer, it will provide us with a new point of view concerning the treatment of this type of tumor. As a result of recent advances for endoscopic procedures, such as endoscopic mucosal resection or endoscopic submucosal dissection, local treatment for early colorectal cancers is generally accepted and widely applied. If intramucosal colon cancers could have risk of metastasis, additional investigation is warranted to define the high-risk group before applying local treatment for these patients.

Lamination of the Masticatory Muscles in the Phascolarctos cinereus (Koala) According to Their Innervations

The masticatory muscles are usually classified into four groups: masseter, temporalis, lateral pterygoid and medial pterygoid. The communicating muscle bundle between the temporalis and masseter called the zygomaticomandibular muscle exists. The laminations within these muscles are commonly separated by aponeuroses. Nerves control the action of muscles, so improved understanding about innervation patterns in the masticatory muscles is important in the consideration of muscle function. In this study, we focus on the relationships between the nerves supply and the lamination of masticatory muscles in Phascolarctos cinereus (Koala). The masseter muscle consists of superficial and deep muscle layers. The superficial muscle layer of the masseter muscle is divided into rostro-lateral and caudo-internal nerve layers. The deep muscle layer of the masseter muscle is divided into rostral, rostro-lateral, medial and caudo-internal nerve layers. The nerves that innervate the zygomaticomandibular muscle are distributed to the lateral area of the coronoid process. The temporalis muscle was divided into internal layer of the coronoid process, a lateral layer of the coronoid process and a posterior layer by the nerve distribution pattern. The medial pterygoid muscle divided into rostro-internal, medial and caudo-lateral nerve layers.

Reliability of Lightguide Spectrophotometry (O2C®) for the Investigation of Skin Tissue Microvascular Blood Flow and Tissue Oxygen Supply in Diabetic and Nondiabetic Subjects

Skin microvascular assessment has progressed to an important evaluation in patients with diabetes mellitus. This study was done to evaluate a new device using micro-lightguide spectrophotometry in the assessment of skin microvascular function. Twenty nondiabetic subjects (age 46.6 +/- 14.8 years; mean +/- SD) and 20 diabetic patients (age 59.4 +/- 8.4 years) participated in repeated microvascular measurements using micro-lightguide spectrophotometry. This technique allows simultaneous, noninvasive measurement of microvascular blood flow and hemoglobin oxygenation (SO(2)) at the same anatomical area in different tissue layers. A skin probe was placed on nonhairy skin at the thenar eminence of the left hand for the measurement of SO(2), and the postischemic reactive hyperemia response (PRH) was measured in skin and underlying muscle tissue. Repeated measurements in PRH revealed a good correlation at the superficial skin layer (r = 0.97, p < 0.0001) with a coefficient of variation at 9.2 +/- 1.7% and at the superficial muscle layer (r = 0.80, p < 0.0002) with a coefficient of variation at 9.7 +/- 1.5%. A slightly weaker correlation was observed for the SO(2) measurement at the skin layer (r = 0.69 +/- p < 0.0001) with a coefficient of variation at 17.5 +/- 3.8% and at the muscle layer (r = 0.48; p = 0.0016) with a coefficient of variation at 18.1 +/- 10.5%. Lightguide spectrophotometry is an easy, noninvasive, and reliable method for simultaneous measurement of superficial microvascular blood flow by laser Doppler fluxmetry and skin oxygenation by spectrophotometry. Further studies are required to clarify the validity of these measures in special patient populations such as diabetes mellitus with specified microvascular complications.

Cell morphogenesis and migration during zebrafish somitogenesis

Somitic cells form the axial skeleton, dermis, and most body musculature. In zebrafish, muscle is the major somitic derivative. As muscle cells mature, they undergo a dramatic cell shape change, transforming into long myofibers that span the distance between adjacent somite boundaries. Cell elongation occurs in a medial to lateral wave in zebrafish, which correlates with and is dependent upon the migration of an early differentiating population of slow muscle fibers. Slow muscle precursors are initially the most medial muscle cells, but after somite formation they migrate laterally through the fast muscle domain and become the most superficial (lateral) muscle layer. By creating a series of genetic mosaics, we show that slow muscle cells trigger elongation of fast muscle neighbors as they pass laterally through the somite, creating a morphogenetic wave that patterns fast muscle elongation in its wake. Just one wild-type slow muscle fiber can rescue elongation of neighboring mutant cells, but not cells in adjacent somites, suggesting that a cell contact-mediated mechanism or a short-range signal relays an elongation cue from one cell to the next. Slow muscle precursors undergo a number of distinctive cell shape changes prior to the migratory event, and we are characterizing these behaviors in detail. In addition, we have identified two actin regulatory molecules expressed in slow muscle cells that are critical for slow muscle cell pre-migratory behaviors. Our current work focuses on characterizing the role of tissue-specific actin dynamics in slow muscle cell elongation and migration and on identifying the molecular nature of the slow-muscle derived elongation trigger. Research supported by NIH, March of Dimes, and a Pew Scholar Award.

Differential distribution of nerve fibers immunoreactive for substance P and calcitonin gene-related peptide in the superficial and deep muscle layers of the dorsum of the rat

We compared the distribution of substance P (SP) and calcitonin gene-related peptide (CGRP) fibers of the superficial muscle layer (trapezius muscle), median muscle layer (rhomboideus muscle), and deep muscle layer (longissimus and spinalis muscles) of the dorsum of the rat. SP- and CGRP-immunoreactive fibers were seen along the walls of various types of blood vessels and within nerve bundles in skeletal muscles of all layers. Coexistence of SP and CGRP was evident in nerve fibers along the blood vessel walls. The total number of CGRP varicosities per millimeter square of muscle surface area was evaluated quantitatively, and CGRP varicosities were found to be significantly more numerous in the superficial muscle layer than in the deeper ones. After capsaicin treatment, most of the SP and CGRP fibers along the blood vessel walls were eliminated. These results suggest that sensory nerve fibers containing SP and CGRP are distributed more abundantly in the superficial muscle layer than in the deeper ones and that they might be involved in the regulation of local blood flow. The finding of SP- and CGRP-immunoreactive nerve fibers along the blood vessel walls connecting the trapezius muscle and the hypodermis raises the possibility that sensory stimuli to the skin affect the local blood flow of superficial muscle through collaterals of cutaneous fibers.

TRANSURETHRAL EN BLOC RESECTION OF BLADDER TUMORS

Transurethral en bloc resection of bladder tumors is desirable for evaluating the pathological depth of bladder tumors in resected specimens. The safety, technique and effectiveness of en bloc resection of bladder tumors was investigated using a holmium laser or knife electrode. A total of 35 patients with transitional cell carcinoma of various sizes underwent transurethral en bloc resection with the muscle layer by holmium laser or knife electrode. The holmium laser was used for tumors at the bladder neck, as in prostate resection, while tumors at the bladder wall were treated with a knife electrode. A circular incision was made around the tumor, followed by level incisions beneath it with subsequent tumor retrieval. The circular incision connected marks made about 10 mm. away from the tumor edge and continued until the superficial muscle layer was visualized. The resected 1 piece specimen was grasped with a loop electrode and retrieved. This technique has been used in 35 consecutive patients (50 lesions). Tissue slides crossing the center of the tumor correctly determined the depth of cancer invasion as stages pTa to pT2. No uncontrollable bleeding, perforation or other serious complications occurred. Transurethral en bloc resection is a safe and useful technique that also provides sufficient material for pathological evaluation.

Spatiotemporal surface EMG characteristics from rat triceps brachii muscle during treadmill locomotion indicate selective recruitment of functionally distinct muscle regions.

Multichannel surface EMG recordings of a multiheaded skeletal muscle during cyclic locomotion combined with cineradiography were analysed in a chronic experiment. The resulting detailed two-dimensional activation pattern from the long and lateral triceps brachii heads of the rat during treadmill locomotion were combined with gait characteristics and fibre typing of the muscle. Shortly before ground contact of the forelimb, maximum muscle activity was found in the proximal part of the long head of the muscle. During the stance phase maximum activity was observed in the proximal part of the lateral head. The frequency dependent behaviour of cross-covariance functions over both muscle heads confirmed this selective shift in activation. In the lateral triceps brachii head of the investigated rats, exclusively type II fibres were found. In the long head the frequency of type I fibres was the highest in the deep muscle layers, proximally more than distally, whereas type II fibres were dominant in more superficial muscle layers. A combination of physiological and histological findings supports an anticipating mechanism whereby fine-tuning of the vertical foot down manoeuvre is mainly achieved by the (type I fibre dominated) proximal deep compartment of the biarticular long triceps brachii head and force generation is predominantly executed by the monoarticular lateral triceps brachii head.

3455 In vivo characterization of colonic thermal injury by the argon plasma coagulator.

The Argon Plasma Coagulator (APC) is a new instrument for non-contact delivery of monopolar electrical energy to mucosal surfaces. It has rapidly gained acceptance for obliteration of vascular lesions and superficial tumors. Depth of injury is thought to be limited through preferential discharge of energy to non-dessicated tissue. However, injury induced by this device has not been well characterized <i>in vivo</i>. Aim: To characterize APCinduced colonic injury in a porcine model. Methods: Swine weighing 50kg were used. Under general anesthesia, a laparotomy was performed and a colotomy incision was made on the antimesenteric border. Burns were made with an APC probe perpendicular to the mucosa at gas-flow 2.4L/min. Variables studied were power (45, 60 & 75W) and duration (1, 2 or 3 seconds), n ≥ 11 for each power/time permutation. Injury was graded histologically as the percentage of coagulation sites per setting yielding severe injury to the superficial circular muscle layer (CML) and deep longitudinal muscle layer (LML). Injury was expressed as the number of burns to CML or LML. Results: The mean surface area of lesions increased with coagulation duration (45W for 1,2 & 3 seconds:184±7mm², 215±1mm², 234±8mm², respectively). CML injury was predicted by power (p=0.01) and duration of burn (p=0.001) and correlated strongly with total energy delivered (r²=0.92). Severe damage to the LML correlated strongly with time of burn (r²=0.99), but poorly with power (r²=0.15); correlation with total energy was less apparent than with CML (r²=0.72). Conclusions: Deep injury correlates more closely with <i>duration</i> of coagulation than total energy delivered. Power setting does not correlate with deep injury. Surface area of the lesion is not proportional to energy delivered. Implication: Limitation of depth of injury with the APC may have been previously overstated, "protective" arcing to non-dessicated tissue does not appear to be significant <i>in vivo</i>. Transmural injury may occur at recommended settings (eg: 45W) if coagulation duration is excessive.

Morphology and Function of Lateral Hypaxial Musculature in Salamanders1

Abstract Synopsis. The lateral hypaxial musculature (LHM) of salamanders may serve as a useful model for understanding the functions of LHM in tetrapods more generally. Salamanders have between two and four layers of LHM, arranged segmentally in myomeres. These layers produce three primary mechanical actions: they bend the body, pressurize the body, and produce or resist torsion about the long axis of the body. The optimum muscle fiber angle for forceful bending is 0° to the long axis, the optimum angle for pressurization is 90°, and the optimum angle for torsion is 45°. For generating bending and torsional moments, lateral (superficial) muscle layers have greater mechanical advantage than medial (deep) layers. For increasing body pressure, by contrast, medial layers have greater mechanical advantage. A comparison of muscle fiber angles in aquatic and terrestrial salamanders reveals that some aquatic salamanders have one muscle layer with a low fiber angle which may represent a specialization for swimming...

AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER: Intravesical Chemotherapy

Superficial bladder cancer accounts for approximately 70% to 80% of all newly diagnosed bladder cancers. The vast majority of these cancers are transitional bladder tumors of various histologic grades (I to III). Superficial tumors include carcinoma in situ (CIS), tumors confined to the epithelium (Ta), and superficial tumors that invade the lamina propria (T1) but do not involve superficial muscle layers. The primary treatment for eradication of stage Ta and T1 bladder cancers is transurethral resection of the tumor. Many patients with superficial bladder tumors treated with endoscopic surgery alone have recurrence or tumor progression at some point in their follow-up, and, in these patients, the need for adjuvant treatment becomes a major concern.

Post‐hatching development of the gut and lateral muscle in the sole

At hatching the gut of sole Solea solea was a primitive epithelial tube which showed vigorous cellular proliferation but only initial regionalization, and no secretory cells. By contrast, at this stage lateral muscle already consisted of a clearly distinct superficial monolayer of parvalbumin‐negative fibres, and a deeper layer of parvalbumin‐positive (presumptive fastwhite) fibres. There were no very small‐diameter fibres present and very few proliferating cell nuclear antigen (PCNA)‐positive nuclei, indicating that new fibres were not being produced at this time. The gut consisted of a distinct pharynx, oesophagus, stomach and intestine by 12 days, further differentiation of the anterior and posterior intestine was seen at 21 days, and morphological differentiation was complete at 2.5 months. Goblet cells containing acidic glycoconjugates were present at 12 days in the pharynx, oesophagus and anterior intestine, and increased in number at later ages. Neutral glycoconjugates first appeared in absorptive (not goblet) cells at 21 days. From 2.5 months neutral glycoconjugates were found in secretory cells throughout all parts of the gut except the stomach and the oesophagus, and by the adult stage the neutral glycoconjugates were the predominant type in the intestinal goblet cells. The difference in parvalbumin expression between the superficial (negative) and deep (positive) muscle layers seen at hatching persisted at all ages, and from 21 days immunostaining for slow isoforms of myosin gave a positive reaction in the superficial monolayer and subsequent slow muscle layer. Hypertrophic growth continued up to the largest subject examined, by posthatching myogenesis occurred in two distinct and relatively brief phases. The distribution of very small diameter muscle fibres and PCNA‐positive nuclei indicated that muscle hyperplasia occurred initially in apical areas of the myotomes (at 12 and 21 days), but this was followed (at 2.5 months) by a second ‘mosaic’ phase of myogenesis as new fibres appeared scattered throughout the deep muscle layer. Hyperplastic growth had ceased by 1 year.

Histochemical and immunohistochemical investigation of muscle fibres in the sturgeon (Chondrostei; Acipenser)

Summary The arrangement and innervation of lateral muscle and adductor mandibulae (AM) complex were examined histochemically and immunohistochemically in the sturgeon Acipenser transmontanus. Lateral muscle was arranged in myotomes in which the superficial slow-red muscle layer and the deep fast-white muscle layer were separated by an intermediate layer of pink muscle. The AM complex was composed of a small slow-red muscle layer, but the bulk of the muscle was composed of fast-white fibres. Pink fibres appeared both in an intermediate layer and scattered throughout the fast-white muscle. The innervation appeared to resemble that of elasmobranchs and some teleosts. Slow-red fibres of lateral muscle were multiply innervated, whereas fast-white muscle fibres were focally innervated at the myoseptal end. Pink fibres of lateral muscle and fast-white fibres of AM were focally innervated in the mid-region of the fibres. There were no significant differences between 5 month old and adult sturgeons except for a much better developed intermediate (pink) layer surrounding the lateral line in the adult.

Valrubicin.

Valrubicin (AD-32) is an N-trifluoroacetyl, 14-valerate derivative of the anthracycline doxorubicin. It has antineoplastic activity which probably results from interference with nucleic acid metabolism by the drug. Valrubicin entered individual cells more rapidly than doxorubicin in vitro. When valrubicin was administered intravesically to patients with bladder cancer, cytotoxic concentrations of the drug penetrated the superficial muscle layer of the bladder. Complete response rates were 18 and 29% in patients with carcinoma in situ of the bladder which was refractory to intravesical BCG in 2 non-comparative trials of prophylactic intravesical valrubicin. In patients with recurrent superficial papillary tumours, the complete response rate was 46%. Adverse events were generally transient in patients who received intravesical valrubicin. Bladder irritation occurred in 88% of patients. Systemic absorption of intravesically administered valrubicin was minimal. Accordingly, systemic adverse events generally occurred in < or =5% of patients. Valrubicin was less toxic to chick embryos and haematopoietic stem cells in vitro and produced a lower incidence of cardiotoxicity in rabbits, compared with doxorubicin.

Penetration of intravesical doxorubicin in human bladders.

The bladder wall penetration kinetics of intravesical doxorubicin were examined in radical cystectomy patients, to provide insight into drug concentrations at target tumor sites. The dosing solution (40 mg/20 ml) was instilled just prior to the start of surgery and maintained for 60-115 min until just prior to bladder excision. The data showed considerable inter-patient variability in the peak plasma concentration (24-fold), urine concentration (7- fold), and tissue concentration (28-fold). The urine concentration at the time of tissue harvest was about 17% of the concentration in the dosing solution. This was due to the dilution by post-catheterization residual urine and urine produced during treatment. The doxorubicin concentration dropped by 32-fold across the urothelium, and declined semi-logarithmically with respect to depth in the capillary-perfused tissues beneath the urothelium with a 50% decrease over about 500 micromole. In three of six patients from whom tumor tissue was obtained, the doxorubicin concentration was higher than the adjacent non-tumor-bearing tissues of comparable tissue depth, whereas the reverse was seen in the remaining three tumors. The plasma concentrations were 0.02, 0.03, 0.05, 0.27, and 0.69% of the concentrations in the tumors, urothelium, lamina propria, superficial and deep muscle layers, respectively. These data indicate: (a) a considerable intra- and inter-patient variability in bladder tissue concentrations, in part due to the variability in the urine concentration; (b) the urothelium is an effective barrier to doxorubicin penetration; and (c) a targeting advantage of intravesical therapy for the treatment of superficial bladder cancer yielding superficial bladder tissue concentrations at least 2000-fold higher than in the systemic circulation. A comparison of the data of doxorubicin with our previously published data on mitomycin C shows similar bladder tissue pharmacokinetics for the two drugs, suggesting that there is no pharmacokinetic preference for either drug.

Melanosis Peritonei Associated with Enteric Duplication Cyst

Melanosis peritonei is extremely rare, and only five cases have been reported in the English literature, four in association with ovarian dermoid cysts, and one with a peritoneal cyst. We describe an additional case occurring in a girl two years of age who also had an enteric cyst. This is the first reported case of melanosis peritonei not associated with an ovarian teratoma, but with an enteric duplication cyst. Melanophages were present focally in the submucosa, superficial muscle layer, and ulcer bases of the cyst and extensively as small nodules on the peritoneal surface and in the omentum. The tendency of perivascular nodular aggregation of melanophages favors a hematogenous (or lymphatic) spread rather than implantation. Although clear evidence of melanocytic aggregation is lacking, are speculate that the melanin originated from the esophageal-like squamous mucosa of the cyst.

Temperature and development in larvae of the turbot Scophthalmus maximus

Turbot (Scophthalmus maximus L.) were reared at 12 and 16°C until 26 d after hatching. At both temperatures, starting at the neural plate stage, somites were initially formed every 75 min. Expressed as a percentage of development time (DT, fertilisation to 90% larvae hatching) somite formation occurred relatively earlier during embryogenesis at 12°C (45% DT) than at 16°C (55% DT). At 12°C, after the 32-somite stage the rate of somite formation decreased to one every 300 min. The larvae hatched after 6 d at 12°C and 3 d at 16°C at a relatively primitive stage of development, prior to the opening of the mouth and anus, with unpigmented eyes, and a straight gut. Temperature altered the relative timing of organogenesis in the larval stages. At 12°C, the following characters appeared (in this order): swimbladder>loop in the gut (at the time of yolk exhaustion)>caudal fin. In contrast, at 16°C, the caudal fin appeared at the same time as the loop in the gut. At 16°C, spines formed on the head in the region of the otic capsule at the time the swimbladder formed and the yolk was exhausted, but were absent in 12°C larvae. At both temperatures, in 1 d-old larvae the myotomes just behind the yolk-sac contained ∼ 200 inner muscle fibres (presumptive white muscle). The initial growth of inner muscle was largely due to hypertrophy, but by 26 d at 12°C and 11 d at 16°C hyperplastic growth became important, as evidenced by a significant increase in the number of small fibres (<10 μm2). By 26 d the average number of inner muscle fibres had increased to 341 at 12°C and 988 at 16°C. New muscle fibres were added in distinct germinal zones at the dorsal and ventral apices of the myotomes. Metamorphosis was associated with a thickening of the superficial (presumptive red) muscle layer and the appearance of tonic muscle fibres.