Frontiers in pediatric testicular torsion: An integrated review of prevailing trends and management outcomes.

Testicular torsion remains the most frequent cause of testicular ischemia, especially in adolescents and young adults. Timely diagnosis and intervention are keys to saving the affected testicle. This review presents current trends in the diagnosis and treatment of torsion, potential pitfalls and consequent outcomes. Additionally, other salient issues surrounding testicular torsion are also discussed, including: pathogenesis of injury, legal ramifications, fertility outcomes, novel management techniques, and recent advances in diagnostic technology.

Bioactive molecules from sea hares.

Sea hares, belonging to the order Opisthobranchia, subclass Gastropoda, are mollusks that have attracted many researchers who are interested in the chemical defense mechanisms of these soft and "shell-less" snails. Numbers of small molecules of dietary origin have been isolated from sea hares and some have ecologically relevant activities, such as fish deterrent activity or toxicity. Recently, however, greater attention has been paid to biomedically interesting sea hare isolates such as dolastatins, a series of antitumor peptide/macrolides isolated from Dolabella auricularia. Another series of bioactive peptide/macrolides, as represented by aplyronines, have been isolated from sea hares in Japanese waters. Although earlier studies indicated the potent antitumor activity of aplyronines, their clinical development has never been conducted because of the minute amount of compound available from the natural source. Recent synthetic studies, however, have made it possible to prepare these compounds and analogs for a structure-activity relationship study, and started to uncover their unique action mechanism towards their putative targets, microfilaments. Here, recent findings of small antitumor molecules isolated from Japanese sea hares are reviewed. Sea hares are also known to produce cytotoxic and antimicrobial proteins. In contrast to the small molecules of dietary origin, proteins are the genetic products of sea hares and they are likely to have some primary physiological functions in addition to ecological roles in the sea hare. Based on the biochemical properties and phylogenetic analysis of these proteins, we propose that they belong to one family of molecule, the "Aplysianin A family," although their molecular weights are apparently divided into two groups. Interestingly, the active principles in Aplysia species and Dolabella auricularia were shown to be L-amino acid oxidase (LAAO), a flavin enzyme that oxidizes an alpha-amino group of the substrate with molecular oxygen and liberates hydrogen peroxide, with a sequence similar to other known LAAOs, including snake venom. Possible antibacterial activity and cytotoxic activity mechanisms of these proteins are also discussed.

Inhibition of experimental metastasis of murine Lewis lung carcinoma by an inhibitor of glucosylceramide synthase and its possible mechanism of action.

In view of the increasing evidence that glucosphingolipids (GSLs) on tumor cell surfaces play an important role in tumor metastasis, an inhibitor of glucosylceramide synthase, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) was used to evaluate the role of GSLs in this respect. Treatment of Lewis lung carcinoma cells with 5 microM D-PDMP resulted in a time-dependent marked decrease in levels of all cellular GSLs (glucosylceramide, lactosylceramide, ceramide trihexoside, globoside, and ganglioside GM3). By 6 days, the total GSL content was reduced to approximately 20% of the level in the untreated control cells and at the same time the lung-colonizing capacity of the PDMP-treated cells in inoculated mice was greatly reduced. Closely associated with the degree of GSL depletion, the ability of the cells to invade reconstituted basement membranes in vitro was also reduced, suggesting that GSLs in tumor cell membranes modulate the cell surface interaction with basement membrane components. In order to assess a possible contribution of the defective capacities to drug-induced suppression of experimental metastasis and invasion, we tested the effect of D-PDMP on attachment and migration to laminin and fibronectin and found that the inhibitor specifically reduced the laminin-mediated attachment and migration, whereas it had no effect on fibronectin-mediated attachment and migration. These effects of the inhibitor on lung colonizing capacity in vivo and the invasion, adhesion, and migration properties of the cells in vitro were reversible within 24 h after removal of the drug. By contrast, L-PDMP (the enantiomeric form of D-PDMP), which has no inhibitory activity on glucosylceramide synthesis, did not cause any of the changes produced by D-PDMP. Together, these results suggest that GSLs in tumor cell membranes are essential for the metastatic spread of tumor cells through basement membranes, modulating the interaction of laminin and its receptors.

GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR.

GPRC5A is an orphan G-protein coupled receptor with an intriguing dual behavior, acting as an oncogene in some cancers and as a tumor suppressor in other cancers. In the pancreatic cancer context, very little is known about GPRC5A. By analyzing messenger RNA (mRNA) expression data from 675 human cancer cell lines and 10 609 samples from The Cancer Genome Atlas (TCGA) we found that GPRC5A's abundance in pancreatic cancer is highest (cell lines) or second highest (TCGA) among all tissues and cancer types. Further analyses of an independent set of 252 pancreatic normal and cancer samples showed GPRC5A mRNA to be more than twofold upregulated in primary tumor samples compared with normal pancreas (P-value<10(-5)), and even further upregulated in pancreatic cancer metastases to various organs (P-value=0.0021). Immunostaining of 208 cores (103 samples) of a tissue microarray showed generally low expression of GPRC5A protein in normal pancreatic ductal cells; on the other hand, in primary and metastatic samples, GPRC5A protein levels were dramatically increased in pancreatic ductal cells. In vitro studies of multiple pancreatic cancer cell lines showed that an increase in GPRC5A protein levels promoted pancreatic cancer cell growth and migration. Unexpectedly, when we treated pancreatic cancer cell lines with gemcitabine (2',2'-difluorodeoxycytidine), we observed an increase in GPRC5A protein abundance. On the other hand, when we knocked down GPRC5A we sensitized pancreatic cancer cells to gemcitabine. Through further experimentation we showed that the monotonic increase in GPRC5A protein levels that we observe for the first 18 h following gemcitabine treatment results from interactions between GPRC5A's mRNA and the RNA-binding protein HuR, which is an established key mediator of gemcitabine's efficacy in cancer cells. As we discovered, the interaction between GPRC5A and HuR is mediated by at least one HuR-binding site in GPRC5A's mRNA. Our findings indicate that GPRC5A is part of a complex molecular axis that involves gemcitabine and HuR, and, possibly, other genes. Further work is warranted before it can be established unequivocally that GPRC5A is an oncogene in the pancreatic cancer context.

The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells.

Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure (pO2) and decreased O2 intracellular perfusion. Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine-threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3'-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR's regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.

Effects of antihypertensive agents on baroreceptor function in early hypertensive rats.

To investigate the effects of antihypertensive treatment with four currently used agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on the arterial baroreceptor function at the early phase of hypertension, we administered the agents to spontaneously hypertensive rats and Wistar-Kyoto rats from 8 to 10 weeks of age and examined the aortic nerve activity function. In untreated spontaneously hypertensive rats, the relation between the arterial pressure and aortic nerve activity was shifted to the right, that is, to a higher pressure level (threshold pressure, 90 +/- 3 versus 76 +/- 1 mm Hg, P < .05), and the maximum gain which was obtained by logistic function analysis was depressed (1.55 +/- 0.08% versus 2.18 +/- 0.13% maximum/mm Hg, P < .01) as compared with untreated Wistar-Kyoto rats. An equivalent decrease in arterial pressure with each of the four agents (-20 +/- 1 mm Hg, P < .01) produced a leftward shift of the arterial pressure-aortic nerve activity relation to a similar extent (threshold pressure, 77 +/- 1 mm Hg, P < .05) in spontaneously hypertensive rats. In addition, treatment with the four agents equally augmented the maximum gain in spontaneously hypertensive rats (2.13 +/- 0.09% maximum/mm Hg, P < .05). The antihypertensive agents affected neither the blood pressure nor the aortic nerve activity in Wistar-Kyoto rats. These findings suggest that antihypertensive treatment with the four classes of agents equally enhances the arterial baroreceptor function through blood pressure reduction but not through specific depressor mechanisms at the early stage of hypertension.

Nitric oxide increases renal blood flow by interacting with the sympathetic nervous system.

To investigate whether changes in renal blood flow induced by nondepressor doses of L-arginine, the precursor of nitric oxide, are mediated by a sympathetic neural mechanism, we examined the following in conscious rabbits: (1) the effects of intravenous infusion of L- or D-arginine (15 to 200 mumol/kg per minute) on renal blood flow and renal sympathetic nerve activity with or without intravenous infusion of a nonpressor dose of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, and (2) the effects of L-arginine on renal blood flow after renal denervation with or without L-NMMA pretreatment. In renal innervated rabbits, L-arginine (100 and 200 mumol/kg per minute) increased renal blood flow by 9 +/- 2 and 16 +/- 3 mL/min (P < .05, respectively) and decreased renal sympathetic nerve activity by 12 +/- 4% and 19 +/- 3% of control (P < .05, respectively). In contrast, no changes occurred in any variable during D-arginine infusion. L-NMMA attenuated the renal blood flow and renal sympathetic nerve activity responses to L-arginine (P < .05). In renal denervated rabbits, L-NMMA also attenuated the renal blood flow responses to L-arginine (P < .05) and abolished them (P < .05) compared with those in renal innervated rabbits. All renal blood flow responses to L-arginine were accompanied by parallel changes in plasma L-citrulline concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of antihypertensive agents on arterial baroreceptor reflexes in conscious rats.

The effects of antihypertensive treatment with four currently used agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on the arterial baroreceptor reflex control of renal sympathetic nerve activity and heart rate were investigated in 45 conscious spontaneously hypertensive rats and 37 age-matched Wistar-Kyoto rats. Antihypertensive agents were administered for 2 weeks beginning at 8 weeks of age to treat and prevent the development of hypertension. Blood pressure was reduced to a similar level (-13 +/- 3 mm Hg, p < 0.05) by each antihypertensive agent. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded in the conscious state during phenylephrine and nitroglycerin ramp infusion. The gain in the baroreceptor reflex was determined from the maximum slope of logistic function curves. Untreated spontaneously hypertensive rats exhibited decreased sensitivity of reflex control of renal sympathetic nerve activity and heart rate (-1.78 +/- 0.07% of control/mm Hg and -2.16 +/- 0.05 beats per minute/mm Hg, respectively) compared with untreated Wistar-Kyoto rats (-3.62 +/- 0.18% of control/mm Hg, p < 0.01, and -3.46 +/- 0.11 beats per minute/mm Hg, p < 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of early and late start of antihypertensive agents and baroreceptor reflexes.

Along with arterial blood pressure reduction, maintenance of the integrity of baroreceptor reflex function contributes to preserving end-organ function in the treatment of hypertensive patients. The purpose of this study was to investigate the effects of antihypertensive agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on baroreceptor reflex function by comparing early and late starts of treatment. We administered each agent to spontaneously hypertensive rats (SHR) as early-start groups from 10 to 36 weeks of age and as late-start groups from 28 to 36 weeks of age. We evaluated the gain of the reflex control of renal sympathetic nerve activity and heart rate using ramp infusions of phenylephrine and nitroglycerin in untreated SHR at 10, 28, or 36 weeks of age and in treated SHR at 36 weeks of age. In 28- and 36-week-old untreated SHR, the renal sympathetic nerve activity gain was not altered and the heart rate gain was decreased (from -2.3 +/- 0.3 to -1.3 +/- 0.3 and -1.2 +/- 0.3 beats per minute [bm]/mm Hg, P < .05, respectively) compared with 10-week-old SHR. Early and late start of therapy produced arterial pressure reductions (-18 +/- 4 and -12 +/- 5 mm Hg, P < .05, respectively). In the early-start groups, the renal sympathetic nerve activity gain was improved markedly in nicardipine- and enalapril-treated SHR (-4.2 +/- 0.2% and -4.9 +/- 0.2% of control/mm Hg, P < .01, respectively), and the heart rate gain was improved markedly in atenolol- and enalapril-treated SHR (-4.1 +/- 0.2 and -4.4 +/- 0.2 bpm/mm Hg, P < .01, respectively). In the late-start groups, the renal sympathetic nerve activity gain was improved moderately in nicardipine- and enalapril-treated SHR (-3.8 +/- 0.2% and -2.9 +/- 0.2% of control/mm Hg, P < .05, respectively). The heart rate gain was improved slightly only in nicardipine-treated SHR (-1.9 +/- 0.2 bpm/mm Hg, P < .05). These results demonstrate that an early start of antihypertensive treatment improves baroreceptor reflex function markedly compared with a late start of treatment. This supports the hypothesis that a possible critical phase sensitive to intervention with antihypertensive treatment exists during the development of hypertension and indicates that the early start of antihypertensive treatment would be required in clinical practice.

Sphingosine inhibits attachment of murine Lewis lung carcinoma cells to laminin and type IV collagen.

The effect of sphingosine (SPH) on the adhesive properties of Lewis lung carcinoma (3LL) cells was investigated using plastic precoated with the extracellular matrix proteins, laminin, fibronectin, or type IV collagen. Treatment of 3LL cells with SPH (0.5-10 microM) resulted in a dose-dependent decrease in the ability to bind to laminin and type IV collagen but had little or no effect on attachment to fibronectin. Phorbol 12-myristate 13-acetate (PMA) selectively enhanced attachment of 3LL cells to laminin and collagen. The inhibitory effect of SPH on attachment to both proteins was competitively antagonized by PMA. These results suggest that SPH acts as a negative effector for cell attachment to laminin and collagen, and that the cell attachment process to both proteins might be regulated in part by protein kinase C.

Expression of ganglioside GM3 and H-2 antigens in clones with different metastatic and growth potentials isolated from Lewis lung carcinoma (3LL) cell line.

In view of the evidence that cell expression of gangliosides in several tumors is positively involved in the metastatic phenotype, Lewis lung carcinoma (3LL) cell line, expressing GM3 as the major ganglioside, was analysed for the cell surface expression of GM3. An indirect immunofluorescence assay, using a M2590 monoclonal antibody recognizing GM3, was used for this purpose. Since the parental 3LL cells consist of heterogenous subpopulations differing in the degrees of GM3 expression, we have developed clones of this cell line with different degrees of metastatic potentials by using an in vitro non-selective procedure in order to investigate whether the expression of GM3 is associated with metastatic potential. The degree of cell surface expression of GM3 among the clones correlated well with their total cellular content of this ganglioside. However, we were unable to confirm the report of increased level of GM3 in high metastatic 3LL clones, nor did a decreased level correlate with weak metastatic ability. In our recent work, an inhibitor of glucosylceramide synthase, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), was found to decrease the levels of all cellular glucosphingolipids and cause the accumulation of the precursors of glucosylceramide. The present study does not, however, rule out the possible involvement of this lipid family in metastatic dissemination, since treatment of 3LL cells with D-PDMP resulted in significant inhibition of their experimental metastatic potential. Clones expressing very low GM3 grew slowly in culture dishes, suggesting that GM3 may have a regulatory role in cell proliferation. The low metastatic clones expressed high levels of H-2Kb antigen, while the expression of the same antigen on the high metastatic clones was relatively low, confirming the previous observation of this tumor system. Moreover, a clone showing the lowest tumorigenic potency revealed both a high cell surface expression of H-2Kb and a high H-2Kb/H-2Db ratio.

Stimulation of glycosphingolipid biosynthesis by L-threo-1-phenyl-2-decanoylamino-1-propanol and its homologs in B16 melanoma cells.

Previous studies have demonstrated that the ceramide analog D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) inhibits glucosylceramide (GlcCer) synthase and thus leads to extensive depletion of glycosphingolipids (GSLs) biosynthesized from GlcCer [reviewed by Radin, N.S., Shayman, J.A., and Inokuchi, J. (1993) Adv. Lipid Res. 26, 183-213). In the present study, stereospecificity of PDMP activity was demonstrated with an enantiomeric pair, D-threo-PDMP and L-threo-PDMP. Treatment of B16 melanoma cells with the D-threo or L-threo isomer produced contrasting changes of GSL biosynthesis, as monitored by metabolic labeling with [3H]Gal. D-PDMP markedly inhibited incorporation of radioactivity into GlcCer, LacCer, and GM3 as expected, whereas the L-threo isomer significantly increased it. Homologs of L-PDMP having different N-acyl chains were synthesized and also tested for their effects. Among them, the compounds having C8-C14 acyl chains increased incorporation of the radioactivity into GSLs to different degrees, demonstrating that the stimulatory effect of the L-threo homologs depends on acyl chain length. In order to elucidate the biochemical mechanisms of these PDMP effects, the activities of GlcCer synthase, LacCer synthase, and GM3 synthase in B16 cell lysates were measured in the presence of PDMP. D-Threo-PDMP but not the L-threo isomer inhibited both LacCer and GM3 synthases as well as GlcCer synthase, suggesting that the ceramide-like structure of the D-PDMP molecule interacted stereospecifically with these GSL-synthesizing enzymes. On the other hand, L-PDMP had no effect in the in vitro assays.(ABSTRACT TRUNCATED AT 250 WORDS)

Protoplast fusion method for efficient transformation of mouse spermatogenic cells.

The efficiencies of methods for introducing DNAs into spermatogenic cells were investigated. The calcium phosphate method has been most commonly used to transfect DNA into cultured cells, but this method severely damages spermatogenic cells. Therefore, we investigated the efficiencies of transfection of spermatogenic cells by DEAE-dextran, modified liposome, and protoplast fusion methods, which seemed to cause less damage to spermatogenic cells than the calcium phosphate method. The protoplast fusion method was the most suitable for transfection of spermatogenic cells.

Development of a new inhibitor of glucosylceramide synthase.

Analogs of the potent inhibitor of glucosylceramide (GlcCer) synthase, D-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4), based on substitutions in the palmitoyl group were made by means of a stereo-selective synthetic method in order to elucidate the role of the hydrophobic portion in both the inhibitory action toward the enzyme and the biological effects. While P4 strongly inhibited GlcCer synthase with an IC(50) of 0.5 microM in vitro, it also inhibited cell growth by 50% at the concentration of 7 microM. The shorter N-acyl chain analogs including decanoyl, octanoyl, and hexanoyl groups showed similar IC(50) values for GlcCer synthase (around 2 microM) but the hexanoyl analog exhibited only a slight inhibitory effect on cell growth, showing the dissociation between GlcCer depletion and cell growth. Several compounds which exhibit similar hydrophobicity to the hexanoyl analog of P4 were subsequently designed. We found that D-threo-1-phenyl-2-benzyloxycarbonylamino-3-pyrrolidino-1-pr opanol (PBPP) was a most potent inhibitor, showing an IC50 of 0.3 microM. In cultured cells, PBPP was able to deplete glycosphingolipids without affecting cell growth or the ceramide level.

Improved inhibitors of glucosylceramide synthase.

An inhibitor of glucosylceramide (GlcCer) synthase, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), has been reported to deplete cells and mice of their glucosphingolipids. This inhibitor has proved useful for the elucidation of the many functions of this lipid family [reviewed by Radin, N.S. & Inokuchi, J. (1991) Trends Glycosci. Glycotechnol. 3, 200-213]. In the present study, we have synthesized homologs of PDMP having different acyl chains (C6-C18) and compared their effectiveness for the inhibition of GlcCer synthase in vitro and their inhibition of GlcCer, protein, and DNA synthesis in cultured MDCK (Madin-Darby canine kidney) cells. Using MDCK homogenates and mouse brain and liver microsomes, we found that the C6 compound was relatively inactive and that the longer chain compounds did not differ much in inhibitory power. However, the use of intact MDCK cells showed that the longer chain homologs were much more effective in inhibiting GlcCer synthesis, cell growth, and incorporation of [3H]thymidine. Tests with two radioactive homologs showed that the inhibitor with a longer acyl chain was taken up much more effectively by MDCK cells and that this difference explains the much greater effectiveness of this homolog in intact cells. The inhibitors were effective when solubilized either with a nonionic detergent or with bovine serum albumin. The extent of decrease in DNA synthesis was not directly proportional to the decrease in cellular glucosylceramide, possibly because only a low level of the glycolipid is needed for DNA synthesis.

A synthetic ceramide analog (L-PDMP) up-regulates neuronal function.

To address the role of brain gangliosides in synaptic activity, the ceramide analogs, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) and its enantiomer, L-PDMP, were used to inhibit and stimulate ganglioside biosynthesis in cultured cortical neurons. Prolonged treatment with both PDMP isomers exhibited opposite effects on functional synapse formation measured by spontaneous synchronized oscillatory activity of intracellular Ca2+ between the neurons: suppression by D-PDMP and facilitation by L-PDMP. Up-regulation of synaptic activity by L-PDMP could be correlated with the slow but robust activation of p42 mitogen-activated protein kinase. Treatment with L-PDMP after transient forebrain ischemia in rats ameliorated the deficit of a well-learned spatial memory by an 8-arm maze task, suggesting a new potential therapeutic approach for neurodegenerative disorders.

Middle cerebral artery stenosis caused by relatively low-dose irradiation with stereotactic radiosurgery for cerebral arteriovenous malformations: case report.

OBJECTIVE AND IMPORTANCE: There have been occasional reports of stenosis or occlusion of major cerebral arteries occurring several years after stereotactic radiosurgery for cerebral arteriovenous malformations. Nevertheless, little information is available regarding the actual irradiation dose to which the affected artery had been exposed. CLINICAL PRESENTATION: We present a patient with arteriovenous malformations who, although asymptomatic, developed remarkable stenosis of the middle cerebral artery trunk (M1) 3 years after gamma knife radiosurgery. The nidus was covered with a 50% isodose volume. A central dose of 36 Gy was used. A gradual decrease in nidus volume had been suggested by 1- and 2-year postradiosurgical neuroimaging examinations. Three-year postradiosurgical angiography revealed severe segmental stenosis of the M1, as well as remarkable nidus shrinkage. INTERVENTION: The actual irradiation dose delivered to the affected portion of the artery, as retrospectively determined using a highly accurate three-dimensional analysis technique, was estimated to be 5.1 to 9.8 Gy. CONCLUSION: This case suggests that a normal major artery, if located close to the target volume, may be affected by low-dose irradiation (10 Gy or even slightly less) delivered with radiosurgery, although a decrease in blood flow through the M1 because of nidus shrinkage or associated stenosis of the distal middle cerebral artery, as well as other unknown factors, may also contribute to proximal M1 stenosis.

A diffuse white matter ischemic lesion appearing 7 years after stereotactic radiosurgery for cerebral arteriovenous malformations: case report.

OBJECTIVE AND IMPORTANCE: Little information is available about radiation-induced complications occurring more than 5 years after radiosurgical treatment for arteriovenous malformations. CLINICAL PRESENTATION: We present a patient with arteriovenous malformations who experienced hemimotor weakness caused by a diffuse white matter necrotic lesion developing 7 years after gamma knife radiosurgery. The original nidus had been too large (24.1 cm3) to be totally covered and irradiated with a peripheral dose of 20 to 25 Gy. Therefore, the lower half of the nidus, which was adjacent to the major feeding artery, had been partially covered with a 30% isodose volume using two target points with an 18-mm collimator. A central dose of 70 Gy was used to obtain 21 Gy at the periphery. Complete nidus obliteration was angiographically confirmed 38 months after radiosurgery. After a 6-year uncomplicated period, this patient experienced a convulsive seizure and then mild right hemiparesis. INTERVENTION: Computed tomography demonstrated a diffuse hypodense area in the left white matter, which had not been revealed by the previous examination. With steroid treatment, this patient achieved clinical improvement, although there was no significant improvement in the computed tomography-demonstrated white matter lesion. CONCLUSION: Although the evaluation of this patient may not be sufficient and further examinations may be necessary, we tentatively conclude that the computed tomography-demonstrated hypodense lesion in this patient is a radiation-related necrotic lesion. Long-term follow-up is crucial, even after the "treatment goal" has been achieved.

Gamma knife radiosurgery for arteriovenous malformations: long-term follow-up results focusing on complications occurring more than 5 years after irradiation.

The detailed long-term follow-up results of 40 patients treated for cerebral arteriovenous malformations with gamma knife radiosurgery are presented, with special reference to postradiosurgical complications that can develop many years after irradiation. The follow-up period after radiosurgery was 54 to 205 months, excluding one mortality, with a mean and a median of 106 and 97 months, respectively. One patient (2.5%) has, to date, refused all neuroimaging follow-up examinations. Complete nidus obliteration was angiographically confirmed in 26 patients (65%) between 1 and 5 years after radiosurgery. In the remaining 13 patients (32.5%), although significant shrinkage of each nidus was angiographically demonstrated, complete obliteration was not attained during a 3- to 7-year period of follow-up after radiosurgery. Among these 13 patients, 1 underwent surgical extirpation of the nidus and 5 underwent second courses of gamma knife radiosurgery between 3 and 6 years after initial treatment; in 3 of the 5 patients, complete nidus obliteration was angiographically confirmed between 1 and 3 years after the second course of radiosurgery. There were no radiation- or arteriovenous malformation-related mortalities. However, we did experience one angiography-related mortality. We also experienced one morbidity (probably caused by hemorrhagic stroke), which developed 5 years after 2-year postradiosurgical angiography had demonstrated complete obliteration, and three radiation-related morbidities, two of which (hemiparkinsonian syndrome and visual field disturbances caused by delayed cyst formation) occurred 5.5 and 7 years, respectively, after irradiation. Furthermore, we observed another two patients who, although asymptomatic to date, showed delayed cyst formation on magnetic resonance imaging 5 and 10 years after irradiation, respectively. In total, 3 (23%) of 13 patients who underwent computed tomography and/or magnetic resonance imaging more than 5 years after radiosurgery showed delayed cyst formation. In conclusion, long-term follow-up, particularly with the use of neuroimaging techniques, is necessary even after the treatment goal has been achieved.

Penetration of intravenous antibiotics into brain abscesses.

INTRA-ABSCESS CONCENTRATIONS OF the intravenously administered latamoxef (LMOX, moxalactam in the United States) and cefotetan (CTT), were studied in 11 patients with intracranial abscess. None of these patients underwent surgical ablation of the abscess. In all cases, the abscess was aspirated, and multiple aspirations were required in five patients. Antibiotic concentrations in 18 aspirates were, therefore, determined by the agar well method. LMOX concentrations in 16 aspirates drawn from nine brain abscess cases ranged from 0 to 10.9 micrograms/ml, with a mean (standard deviation) of 4.18 (3.04) micrograms/ml. The CTT concentration in one patient with a brain abscess was 8.51 micrograms/ml, and the LMOX concentration in the one remaining patient with subdural empyema was 5.20 micrograms/ml. In one patient, the serum-to-pus penetration rate of LMOX was estimated to be 0.11 against the peak value of the concentration in serum or 0.44 against the simultaneously obtained level in serum. Significantly higher concentrations of LMOX were produced in abscess cavities with multiple-dose administration or by prior drainage of pus. More-advanced stages of local inflammation, as demonstrated by computed tomography, correlated with higher concentrations. However, the routine indexes of systemic inflammation, such as body temperature, white blood cell count, and level of C-reactive protein in serum, cannot be used to predict the concentration present in intracerebral pus. A tendency for LMOX concentrations in pus obtained after single dose-administration to decrease with increasing duration from symptom onset to sampling was observed but was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)