Transcranial focused ultrasound for the treatment of tremor: A preliminary case series.

BACKGROUND: Essential tremor (ET) can be debilitating. Treatments for ET include beta-blockers and surgical interventions. Low-intensity focused ultrasound (LIFU) may offer an office-based non-invasive alternative. OBJECTIVE: This pilot open label clinical trial explores safety, feasibility, and potential efficacy of LIFU in treatment of ET. METHODS: We report outcomes from the first 10 participants in this IRB-approved trial of LIFU for treatment of ET. The ventral intermediate nucleus of the thalamus (Vim) was targeted using structural and functional MRI. Participants underwent eight 10-min sessions of LIFU targeting the contralateral (Vim) to the most affected hand. Safety was closely monitored; Global Rating of Change (GRC) and The Essential Tremor Rating Scale (TETRAS) scores were collected. RESULTS: No adverse effects were reported. Eight participants reported a GRC ≥2. TETRAS performance subscale demonstrated clinically significant improvement in all participants. CONCLUSION: Preliminary findings support LIFU's safety and feasibility. The potential efficacy encourages additional sham-controlled studies.

Use of transcranial low-intensity focused ultrasound for targeted delivery of stem cell-derived exosomes to the brain.

The blood-brain barrier (BBB) presents a significant challenge for targeted drug delivery. A proposed method to improve drug delivery across the BBB is focused ultrasound (fUS), which delivers ultrasound waves to a targeted location in the brain and is hypothesized to open the BBB. Furthermore, stem cell-derived exosomes have been suggested as a possible anti-inflammatory molecule that may have neural benefits, if able to pass the BBB. In the present study, transcranial low-intensity focused ultrasound (LIFU), without the use of intravenous microbubbles, was assessed for both (1) its ability to influence the BBB, as well as (2) its ability to increase the localization of intravenously administered small molecules to a specific region in the brain. In vivo rat studies were conducted with a rodent-customized 2 MHz LIFU probe (peak pressure = 1.5 MPa), and injection of labeled stem cell-derived exosomes. The results suggested that LIFU (without microbubbles) did not appear to open the BBB after exposure times of 20, 40, or 60 min; instead, there appeared to be an increase in transcytosis of the dextran tracer. Furthermore, the imaging results of the exosome study showed an increase in exosome localization in the right hippocampus following 60 min of targeted LIFU.

Laparoscopic pyelopyelostomy for retrocaval ureter without excision of the retrocaval segment: first report of 6 cases.

PURPOSE: We report our series of 6 cases of retrocaval ureter that were successfully treated with a laparoscopic approach. MATERIALS AND METHODS: Three men and 3 women with a mean age of 31 years (range 16 to 50) were referred to our department with a diagnosis of retrocaval ureter. One patient had a 12 mm renal pelvic calculus. A transperitoneal laparoscopic approach was used in all cases. The retrocaval segment along with some of the more proximal and distal segments of the ureter was readily mobilized. The distal part of the dilated renal pelvis was transected and the divided distal segment was repositioned to lie anterior to the inferior vena cava. The renal pelvic stone in 1 patient was readily removed at this point. Re-anastomosis was then performed over a Double-J stent placed intraoperatively using 2 rows of running 4-zero polyglactin sutures with intracorporeal knot tying. The stent was removed 4 weeks later. Excretory urography was performed 3 months after the laparoscopic procedure. RESULTS: Mean operative duration was 180 minutes (range 150 to 210). Patients were discharged home at a mean of 4 days (range 3 to 5). Followup excretory urogram 3 months after laparoscopic repair revealed a widely patent anastomosis with considerable improvement in hydronephrosis in all patients. CONCLUSIONS: To our knowledge this is the largest series of laparoscopic repair of retrocaval ureter reported to date. Laparoscopic pyelopyelostomy for retrocaval ureter without excision of the retrocaval segment is associated with an excellent outcome, minimal postoperative morbidity, short hospital stay and highly satisfactory cosmetic results.

Pedicular vascular control in laparoscopic living donor nephrectomy: The use of clips instead of stapler in 341 donors.

PURPOSE: To demonstrate a less expensive approach for laparoscopic donor nephrectomy. MATERIALS AND METHODS: Left donor nephrectomy was done transperitoneally in flank position. Renal vein and artery were exposed and prepared for nephrectomy. Nondisposable trocars and instruments were used. The adrenal vein was clipped and its arteries were bipolar coagulated. Both renal artery and vein were clip-ligated using three medium large nonautomatic metallic clips and divided, instead of using rather expensive vascular endostapler. Kidney was hand-extracted from suprapubic incision (no Endobag was used). RESULTS: Donor nephrectomy was performed in 341 donors. Mean warm ischemia time was 8.17 minutes. Mean operative time was 260.3 minutes. Conversion and reoperation was required in 2.1% and 3.8% of donors, respectively. Ureteral complications were observed in 2.1% of recipients. No vascular accident occurred from pedicular vessels. One-year graft survival in recipients was 92.6%. By this approach, at least $600 was saved in each nephrectomy. CONCLUSION: Laparoscopic donor nephrectomy can be performed with a less expensive setup without adverse effects on graft outcome. Vascular control using nonautomatic clips instead of more costly vascular endostapler and also hand extraction of the kidney is safe, practical, and economical.

Laparoscopic management of ureteropelvic junction obstruction by division of anterior crossing vein and cephalad relocation of anterior crossing artery.

PURPOSE: We report our experience with laparoscopic management of ureteropelvic junction (UPJ) obstruction by division of the anterior crossing vein and cephalad relocation of the anterior crossing artery. PATIENTS AND METHODS: We used this laparoscopic approach in four male and six female patients with UPJ obstruction associated with anterior crossing vessels. The mean age of the patients was 31.9 years (range 14-59 years). The obstruction was present on the right side in four and on the left side in six patients. Using a transperitoneal approach, the crossing vein was divided, while the crossing artery was preserved, relocated cephalad, and fixed to the peripelvic tissues with metal clips or sutures. Because a grossly normal appearance of the UPJ and upper ureter together with proper pyeloureteral peristalsis and complete renal pelvic emptying were observed intraoperatively, dismembered pyeloplasty was not performed in any of these patients. Diuretic renography and intravenous urography were performed 3, 6, and 12 months postoperatively. RESULTS: The mean operative duration was 140 minutes (range 100-170 minutes). The mean hospital stay was 2.9 days (range 2-5 days), and the mean follow-up was 9.1 months (range 3-22 months). Diuretic renography revealed absence of obstruction in all patients, and intravenous urography showed considerable improvement of the hydronephrosis. CONCLUSION: Select cases of UPJ obstruction associated with anterior crossing vessels seem to be amenable to laparoscopic management by division of the crossing vein and cephalad relocation of the crossing artery. Laparoscopy as a minimally invasive approach may offer a better opportunity to evaluate the role of anterior crossing vessels in UPJ obstruction.

Interferon-alpha2a and 13-cis-retinoic acid with radiation treatment for high-grade glioma.

Interferon-alpha (IFN-alpha) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-alpha and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-alpha2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-alpha2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-alpha2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy x 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-alpha2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-alpha2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-alpha and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-alpha2a and radiation therapy in a previous trial. In the high-risk group of patients in the present study, concurrent treatment with IFN-alpha2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-alpha2a, or compared with radiation therapy alone in other trials.

Treatment of kidney cancer with autologous tumor cell vaccines of short-term cell lines derived from renal cell carcinoma.

BACKGROUND: We established short-term cultures of autologous tumors from patients with renal carcinoma for use as active specific immunotherapy (i.e., autologous vaccine). METHODS: Between 9/91 and 9/99 the cell biology laboratory of the Hoag Cancer Center received 69 kidney tumor samples that had been surgically excised, including 43 primary tumors and 26 metastatic lesions. Efforts were made to establish short-term tumor cell cultures to use as autologous tumor cell vaccines. Prior to treatment, patients underwent a baseline skin test for delayed tumor hypersensitivity (DTH) and then received s.c. injections of 10 million irradiated tumor cells that were given with various adjuvants weekly x3 and then monthly x5. RESULTS: Cell lines were established for 55/69 patients (80%) including 36/43 (84%) from primary tumors and 19/26 (73%) from distant metastases. Vaccines were prepared for 41 patients; 27 were treated. At the time of this analysis, follow up data was available for 26 patients with a median follow up > 5 years. Treatment was well-tolerated. Of 10 patients who had no evident disease at the time of treatment, nine were alive 1-8 years later; 5/8 had conversion of their DTH test from negative to positive. For 16 patients with measurable metastatic disease at the time of treatment, there were no objective tumor responses; their median survival was 5.0 months. Among these 16 patients, only 1/8 DTH tests converted, but three had a positive baseline DTH test; one was previously treated with interleukin-2 and tumor infiltrating lymphocytes and two others were previously treated with autolymphocyte therapy. CONCLUSIONS: Vaccine therapy with short-term cultures of autologous tumor cells is feasible, well-tolerated and associated with conversion of DTH and long-term survival in patients who are free of disease at the time treatment is initiated. However, significant anti-tumor responses were not seen in patients with measurable disease at the time vaccine treatment was initiated.

Early capsular distension syndrome after sulcus implantation of intraocular lenses.

Two cases of early capsular distension syndrome (cds) are presented. the first occurred after sulcus implantation of a 12.0 mm poly(methyl methacrylate) iol (5.0 mm optic, 10 degree anterior angulation). the second case occurred after sulcus implantation of a foldable silicone iol with optic capture (6.0 mm optic, no anterior angulation). both cases resolved after a neodymium:YAG laser anterior capsulotomy. Cataract surgeons should be aware of the possibility of CDS after sulcus implantation of an IOL in the presence of an intact capsulorhexis and posterior capsule. A small capsulorhexis and in-the-bag capture of the IOL optic are major predisposing factors in this setting.

Pseudoexfoliation syndrome in central Iran: a population-based survey.

PURPOSE: To determine prevalence and clinical characteristics of pseudoexfoliation syndrome (PES) in central Iran in a population-based survey. METHODS: A random sample of people aged 50 years or older from Falavarjan county, central Iran, was examined for signs of PES. RESULTS: Eight hundred-six eyes belonging to 405 cases (210 women and 195 men) were examined. Seventy-seven eyes (9.6%; 95% C.I. = 7.6%-11.6%) of 53 cases (13.1%; 95% C.I. = 9.8%-16.4%) showed pseudoexfoliative deposits. Anterior lens capsule was the most common site for deposition of pseudoexfoliative deposits. Several pigmentary signs were significantly associated with presence of PES (p < 0.001 for all signs). Ten out of 77 eyes (13%) with PES demonstrated increased intraocular pressure or glaucoma. CONCLUSION: Pseudoexfoliation syndrome is a frequent finding in the elderly in central Iran. Most cases can be diagnosed by a careful examination of the anterior lens capsule after pupillary dilation. Glaucoma or ocular hypertension is not common in people with PES in central Iran.

The feasibility of using short-term cultures of ovarian cancer cells for use as autologous tumor cell vaccines as adjuvant treatment of advanced ovarian cancer.

OBJECTIVE: We have tried to establish short-term cultures of autologous tumors from patients with stage III and IV ovarian cancer, which could be used as active specific immunotherapy, (i.e., autologous vaccine) in such patients after debulking surgery & combination chemotherapy. METHODS: Between 5/93 and 11/97 the Hoag cell biology laboratory received 53 ovarian tumor samples that had been surgically excised at the time of laparotomy, and four samples of malignant ascites. Efforts were made to establish short-term tumor cell cultures as confirmed by morphology & phenotype. RESULTS: Short-term proliferating cultures were successfully established from 21/57 samples [37%] which included 8/24 [33%] successes from samples obtained at diagnosis compared to 13/33 [37%] samples obtained at the time of a relapse [p = 0.45]. The probability of successful culture was not related to tumor size for samples with a range of 0.8-34 g (mean 5.8 g). One patient was treated in the setting of metastatic disease and one in the adjuvant setting; both received repeated injections of irradiated autologous tumor cells plus granulocyte macrophage stimulating factor (GM-CSF). In one patient a delayed tumor hypersensitivity skin test converted from negative to positive. CONCLUSIONS: Short-term cultures of autologous tumor cells for use as tumor cell vaccines can be established for about one-third of patients with ovarian cancer using this methodology and the treatment approach is feasible.

Comparison of methods to detect visual field progression in glaucoma .

OBJECTIVE: The purpose of the study is to develop alternative statistical approaches for evaluating the trend of visual field series over time and to compare the results to human observers. DESIGN: Retrospective analysis of visual field results. PARTICIPANTS: Eighty-three eyes of 83 patients (phakic or pseudophakic) with open-angle glaucoma and 5 or more eligible fields were included in the study. INTERVENTION: Three experienced observers independently reviewed the field series to determine stability or progression. MAIN OUTCOME MEASURES: The following additional methods to determine progression of visual field loss were used: (1) pointwise univariate regression analysis and a glaucoma change analysis; (2) univariate regression analysis on visual field indices mean deviation, corrected loss variance, and glaucoma pattern index; (3) pointwise multivariate regression analysis with fixed effects on panel data; and (4) clusterwise multivariate regression analysis with fixed effects on panel data. The results of different statistical methods were compared by determining the pairwise agreement (Cohen's weighted kappa) between each technique and three experienced observers. RESULTS: Patients were observed for a mean (+/-standard deviation) of 5.6 (+/-1.4) years. The visual fields of 27 (33%) and 56 (67%) eyes were considered to have progressed or remained stable, respectively, based on agreement of at least 2 of 3 observers. Univariate regression analysis on visual field indices was not useful for detection of visual field progression. Pointwise and clusterwise regression analyses with fixed effects on panel data performed as well as pointwise univariate regression analysis compared with human observers (kappa = 0.52, 0.53, and 0.55, respectively). Both methods showed better agreement with human observers than with glaucoma change analysis (kappa = 0.41). CONCLUSIONS: A new statistical model, multivariate regression analyses with fixed effects on panel data, is an appropriate method to evaluate the course of visual field series over time and shows reasonable agreement with experienced observers and pointwise univariate regression analysis.

Automatic detection of glaucomatous visual field progression with neural networks.

OBJECTIVE: To evaluate computerized neural networks to determine visual field progression in patients with glaucoma. METHODS: Two hundred thirty-three series of Octopus G1 visual fields of 181 patients with glaucoma were collected. Each series was composed of 4 or more reliable visual fields from patients who had previously undergone automated perimetry. The visual fields were independently evaluated in a masked fashion by 3 experienced observers (K.N.-M, M.W., and J.C.) and were judged to show progression based on the agreement of 2 observers. The stable and progressed series were matched for mean defect at baseline. The threshold data were submitted to a back propagation neural network that was trained to classify each series as stable or progressed. Two thirds of the data were used for the training and the remaining one third to test the performance of the network. This was repeated 3 times to classify all of the series (changing the training and test series). RESULTS: Fifty-nine series of visual fields showed progression and 151 were judged stable. Neural network sensitivity was 73% and specificity was 88% (threshold for progression = 0.5). The concordance of the neural network with the observers was good (0.50 < or = kappa > or = 0.64). CONCLUSIONS: A neural network can be trained to recognize visual field progression in good concordance with experienced observers. Neural networks may be used to aid the physician in the evaluation of glaucomatous visual field progression.

Outcomes of trabeculectomy for primary open-angle glaucoma.

PURPOSE: To determine the long-term functional and structural outcomes in patients treated with trabeculectomy for primary open-angle glaucoma. METHODS: Records of 78 consecutive patients (78 eyes) who had their first trabeculectomy were studied retrospectively (duration of follow-up, 25 to 112 months). Serial automated perimetry and stereoscopic optic disc photographs were used to assess the long-term efficacy of trabeculectomy to prevent progressive glaucomatous damage. Stereoscopic optic disc photographs were available for 29 eyes (38%). Criteria for intraocular pressure control were a minimum intraocular pressure reduction of 20% and intraocular pressure at or below 20 mmHg. RESULTS: There was no evidence of progression of glaucomatous damage in 81% and 65% of the eyes after 3 and 6 years, respectively. The visual field deteriorated in 16 eyes (21%) and progressive structural optic nerve damage occurred in 4 eyes (5%) during follow-up. Deterioration of the optic nerve head in the absence of visual field progression was detected in three (4%) of those eyes. In 19 eyes (25%), further glaucoma surgery was performed. The probability of successful intraocular pressure control after a single operation was 48% and 40% at 3 and 5 years, respectively. CONCLUSION: Progressive glaucomatous damage occurs in about one third of eyes with moderate to severe primary open-angle glaucoma over a 6-year follow-up after trabeculectomy.

The integration of high-dose chemotherapy and biotherapy: initial 5-year experience with autologous bone marrow transplantation in a comprehensive community cancer center.

Perhaps the best example of the integration of chemotherapy and biotherapy is autologous stem cell rescue following high dose chemotherapy. This analysis was undertaken to determine the outcome for patients treated in an autologous bone marrow transplant program, which was initiated in January 1989, and to illustrate the impact which biological response modifiers have had on the toxicity, survival, and costs associated with this aggressive treatment approach. Patients with metastatic cancer and good performance status were treated according to disease-specific treatment protocols. Peripheral blood stem cells [PBSC] came into use in 1990, hematopoietic colony stimulating factors [CSFs] in 1991. Outcome was monitored prospectively from the inception of the program. Five years after the program's inception, 75 patients had undergone 96 intensive chemotherapy treatments followed by autologous PBSC rescue. This included 35 patients with breast cancer, 15 with lymphoma or Hodgkin's Disease, five ovary, four melanoma, three sarcoma, three lung cancer, three leukemia, three testicular, two myeloma, one non-lung small cell carcinoma, and one medulloblastoma. Twenty-one patients underwent back-to-back cycles of intensive therapy and rescue; 14 of whom had breast cancer. Twelve patients were treated in 1989, 14 in 1990, 18 in 1991, 14 in 1992, and 17 in 1993. While four of the first 12 patients died within 60 days of reinfusion of cells in 1989, no patients have died within this time frame as a direct result of therapy during the subsequent four years. No patients have been lost to follow-up. Median survival was only eight months in 1989, but has not been reached for subsequent years. For all patients, median failure-free survival (FFS) is 17.2 months; 1-year FFS is 57%, 2-year 36%, and 3-year 29%. Median overall survival (OS) is 30.4 months; 1-year OS 66%, 2-year 52%, and 3-year 42%. From 1990-1993, for patients with metastatic breast cancer (21), and recurrent lymphoma (15), FFS and OS are comparable to the best results published from academic teaching hospitals. Twenty-one patients have survived over two years, 18 of whom continue in remission. Patients were hospitalized for an average of 31 days in 1989, 28.9 in 1990, 24.5 in 1991, and only 13.0-14.0 days in 1992-1993. Two patients were treated entirely as outpatients. Average hospital charges for the 96 treatments have been $120,000 with a range of $15,000 to $461,000, and currently average around $100,000.(ABSTRACT TRUNCATED AT 250 WORDS)

Evolution of host cell RNA into efficient template RNA by Q beta replicase: the origin of RNA in untemplated reactions.

Q beta replicase can replicate a single molecule of certain species of RNA to 10(14) copies in minutes. This replication ability has been used for in vitro studies of molecular evolution and is currently being utilized as a method of amplifying RNAs that contain probe sequences. It has been observed that Q beta replicase can produce replicatable RNA even in the absence of exogenously added template RNA. The origin of this RNA has been ascribed either to contamination with replicatable RNA or to an ability of Q beta replicase to synthesize RNA de novo from the nucleotides present in the reaction. Technologies that employ Q beta replicase require a thorough understanding of the conditions that lead to this so-called spontaneous RNA production. We have created an expression system and purification method with which we produce gram quantities of highly purified Q beta replicase, and we have identified reaction conditions that prevent the amplification of RNA in assays that do not contain added RNA. However, when these reaction conditions are relaxed, spontaneous RNA replication is seen in up to 100% of the assays. To understand the origin of this RNA, we have cloned several spontaneously produced RNAs. Sequence analysis of one of these RNAs shows that it arose by the evolution of Escherichia coli tRNA into a replicatable template and not by de novo synthesis from nucleoside triphosphates in the reaction.

Macular grid photocoagulation in persistent macular edema due to central retinal vein occlusion.

AIM: Macular edema is still the main cause of poor visual prognosis in central retinal vein occlusion (CRVO). This study was designed to establish whether grid photocoagulation is effective in the management of this disorder. METHODS: The records of 16 patients who had undergone macular grid photocoagulation for persistent macular edema due to CRVO were reviewed retrospectively. Pre-treatment visual acuity ranged from 20/400 to 20/40, and laser treatment was done six months or more after the onset of the disease. RESULTS: Biomicroscopy and fluorescein angiography showed the improvement or disappearance of macular edema in 14/16 patients (87.5%). Improved visual acuity was observed in eight (50%) and no improvement or reduced vision in the other eight (50%). A poorer prognosis was statistically correlated with older age (p < 0.03), macular ischemia (p < 0.001), foveal avascular zone larger than 1/2 disc diameter (p < 0.05) and pigmentary clumps in the foveal area (p < 0.05). Laser treatment was ineffective for most patients with systemic vascular risk factors and pre-treatment visual acuity below 20/200. CONCLUSION: Macular grid photocoagulation may be effective for drying up, or at least reducing, macular edema due to CRVO and some improvement of vision can be expected in half the cases.

[Epidermoid cyst of the testis. Apropos of a case]. / Kyste épidermoïde du testicule. A propos d'un cas.

The epidermoid cyst of the testis, a rare and benign tumour, continues to create problems. Its definitive diagnosis remains a histopathological one and alters the prognosis and therapy. Based on their case report and a literature review, the authors discuss the different diagnostic, prognostic and therapeutic aspects of this lesion.