Delivery systems for the treatment of proliferative vitreoretinopathy: materials, devices and colloidal carriers.

Proliferative vitreoretinopathy (PVR), the most serious complication causing retinal detachment surgery to fail, is one of the leading causes of vision-loss in developed countries. The pharmaceutical treatment of this disease, located in the posterior segment of the eye, is problematic because it is difficult to achieve effective drug levels in the vitreous and the retina through conventional forms of administration (topical or systemic). Intravitreal injections can deliver drugs to the retina without the side-effects associated with systemic administration. However, because PVR is a long-term complication and the half-life of most drugs in the vitreous cavity is short, repeated injections are needed but this can cause complications. Recent advances in ocular drug delivery methods and the development of novel bioactive compounds could lead to new ways for the treatment of PVR. This review will summarize recent literature concerning intraocular drug delivery of biopharmaceutical agents for the treatment and prevention of PVR.

Aggregation Behavior in Aqueous Solutions of a New Class of Asymmetric Bipolar Amphiphiles Investigated by Surface Tension Measurements.

Two series of amphiphilic derivatives of lactose have been synthesized. Tensiometric investigations of the critical micellar concentration (CMC) and the area per molecule at interface (calculated by the Gibbs equation) of aqueous solutions were performed. The values measured depend on the number of methylene groups of the alkyl spacer n and that of the side chain m as well as on the ionic strength and temperature. The results show a behavior closely related to that of gemini surfactants: (1) self-assembly phenomena occur at concentrations below 1 mM, (2) at constant n log CMC increases linearly with higher m, and (3) the influence of the temperature on the aggregation phenomenon is comparable. Copyright 2001 Academic Press.

Synthetic neoglycolipids for biological applications: correlation between their structures and their interactions with membrane proteins.

Synthetic glycolipids are of interest for their biological applications requiring interactions with membrane proteins. Depending on their structures, new series of glycolipids have applications in extraction of membrane proteins or medical applications as mimics of natural ligands of proteins.

Choroid plexus papillomas in infancy and childhood.

The present study deals with 15 cases of choroid plexus papilloma, out of approximately 500 cases of brain tumors observed in children up to 16 years old. Several features are considered, including clinical symptoms and signs--mostly related to increased intracranial pressure--radiological diagnosis, pathology and surgical treatment, and results. Surgery may be radical in most cases, with the exception of histologically malignant papillomas. The management results are usually satisfactory. An adequate choice of surgical approach is mandatory and surgical technique should be meticulous, also in order to avoid the risk of intraoperative tumoral seeding.

Treatment of trigeminal neuralgia by thermocoagulation, glycerolization, and percutaneous compression of the gasserian ganglion and/or retrogasserian rootlets: long-term results and therapeutic protocol.

From 1976 to 1986, 681 patients with drug-refractory trigeminal neuralgia (TN)--typical in 641, symptomatic of multiple sclerosis in 23 and of tumor in 10, atypical in 5, and postherpetic in 2--were treated with various percutaneous procedures. Controlled differential thermocoagulation of the gasserian ganglion and/or retrogasserian rootlets was performed in 533 patients; glycerolization of the trigeminal cistern in 32; and compression of the gasserian ganglion by balloon catheter in 159. Results and complications of each procedure are assessed at a mean follow-up of 6.5 years for thermocoagulation, 5 years for glycerolization, and 3.5 years for compression. The following therapeutic protocol is proposed: 1) in TN patients at first operation: a) gasserian compression (or glycerolization, if experience warrants it) is indicated in all cases of typical TN, unless the 3rd division alone is affected; b) in the latter case and in symptomatic TN, we suggest thermocoagulation; 2) in recurrences: a) after glycerolization or gasserian compression, gasserian compression (or glycerolization) is indicated; b) after thermocoagulation or open surgery, thermocoagulation is suggested.

Multiple intracranial meningiomas.

The authors report 14 cases of multiple intracranial meningiomas representing 1.1% of all meningiomas operated on at their hospital in the past 35 years. Differentiation of multiple meningiomas, especially from meningiomatosis, must be strict. Since the introduction of computerized tomography scanning, the frequency of these cases has risen from 0.58% to 4.5% in the authors' meningioma series. Despite the multiplicity of sites, multiple meningiomas do not differ in prognosis from benign solitary meningiomas.

Tentorial meningiomas: surgical experience with 61 cases and long-term results.

The authors report their experience and long-term results in the surgical treatment of 61 tentorial meningiomas. These cases were operated on between 1951 and 1985 and represented 4.8% of all intracranial meningiomas operated on in that period. The mean duration of clinical history was 29 months, except for cases of meningioma of the posteromedial border, for which it was 5 years. Plain x-ray films and cerebral angiograms were obtained in all cases. Computerized tomography, performed in the last 20 cases (32.7%), supplied much better lesion topography and early diagnosis. The tumor site was posterolateral in 26 cases (42.6%), anterolateral in 14 (22.9%), posteromedial in eight (13.1%), at the free border in seven (11.4%), and in the tentorium itself in six (9.8%). Lateral and medial tumors with solely or mainly supratentorial development were approached from above. The approach from below was reserved for meningiomas with subtentorial involvement only. In meningiomas with both supra- and subtentorial growth, a supratentorial bone flap was combined with a suboccipital craniectomy using a retromastoid incision. The mortality rate was 9.8%. Of the remaining 42 patients, who were followed for at least 5 years, long-term results were good in 26 cases (61.9%), fair in 11 (26.2%), and poor in five (11.9%). Postoperative complications arose in 34% of the patients, but cleared in 27%.

Patient characteristics and pre-operative therapeutic modalities.

The International Cooperative Study on the Timing of Aneurysm Surgery included 68 participating centers from 16 different countries. Eight Italian neurosurgical units participated in the Study: Bellaria Hospital, Bologna; Neurological Institute of Milan, Milan; University Hospital, Brescia; University of Milan, Milan; University of Padova, Padova; University of Rome, Rome; Civil Hospital, Verona; and Civil Hospital, Vicenza. The overall case contribution from the Italian centers was 485 cases, 14.1% of the total study population. As compared to the other centers included in the Study, the Italian centers exhibited a higher percentage of patients with impaired consciousness; a later interval of planned surgery from SAH; frequent use of preoperative lumbar drainage, as well as antihypertensives, anticonvulsants, antifibrinolytics, steroids, diuretics and LMW dextran; and less frequent use of sedatives and narcotics. The individual Italian centers differed significantly in regard to patient characteristics and preoperative therapeutic modalities. There was a relatively high number of stuporous or comatose patients admitted to Centers 1, 7 and 8, very few admitted to Centers 5 and 6, and none admitted to Center 2. The different distribution of key prognostic factors prevents a direct comparison of the overall management results of the centers. A stratification of the patients according to a risk scale and/or a prognostic model is required for comparison of the management results.

Surgical findings and postoperative therapeutic modalities.

The 8 Italian centers participating in the International Cooperative Study on Timing of Aneurysm Surgery operated upon 68% of their patients eligible for the study. This low operative rate is mainly explained by the prevailing use of a delayed surgical policy. Only 28% of cases were operated on within 3 days of hemorrhage. Although early surgery was applied in more than 50% of patients from Centers 2, 6 and 7, most other centers operated on approximately 10% of patients within this time interval. Italian centers exhibited a wide variation in planned and actual surgery interval, with only 48% of their patients eventually operated on at the planned time. Differences from planned and actual timing of surgery were less consistent in the units performing early surgery. Preoperative conditions were different between the individual centers. The percent of patients alert at the time of surgery varied from approximately 50% in Centers 3 and 7 to 90% in Center 5. Centers 2 and 6 never operated on comatose patients and rarely stuporous patients. During surgery, induced hypotension was used in 67% of Italian patients. The brain was tight at exposure in 42% of patients from Italian centers; the difference from the other study centers was very significant (p = 0.0009). Consequently major brain resection was more frequently performed in Italy than in the other centers. Brain conditions depended mainly upon timing of surgery and preoperative grade (except for comatose patients) and varied accordingly between the individual centers. Temporary arterial occlusion was rarely used in Italian centers. Intraoperative bleeding from the aneurysm was slightly more frequent than in the other centers. The overall incidence of intraoperative complications was unremarkable. There were significant differences between the Italian and the other centers regarding the use of postoperative routines and medications. In Italian centers ventricular CSF drainage, shunt insertion, ICP monitoring, sedatives and analgesics were less frequently used; lumbar CSF drainage, anticonvulsants, steroids, and diuretics were applied more frequently. In the individual centers the major differences were in the use of antihypertensives, vasopressor agents, diuretics, hypervolemia, and low-molecular weight dextran.

Results of treatment.

Overall results of management in patients admitted to the 8 Italian centers participating in the International Cooperative Study on Timing of Aneurysm Surgery were rather unsatisfactory, with good recovery in only 42% of patients, and death in 45% of patients. As compared to the other centers included in the Study, Italian centers exhibited a significantly lower recovery rate and a significantly higher mortality rate. There were significant differences also between the individual Italian centers; independently of admission neurological status and timing of surgery, the outcome was better in centers 2 and 6 (a mortality rate under 20%) and worse in centers 1 and 8 (a mortality rate around 60%). Using prognostic factor models, higher than expected mortality rates were observed in 4 centers, and lower than expected good recovery rates in 3 centers. In Italian centers vasospasm accounted for the highest morbidity and mortality rate; the difference in mortality rate from vasospasm between Italian and other centers was very significant. Other important causes of death and disability were constituted by direct effect of the initial bleed and by recurrent hemorrhage. Patients operated on in Italian centers exhibited a good recovery in 57% of cases; the mortality was 27%. Differences from the other centers were less marked than for the overall management results. Mortality rates from vasospasm and from surgical complications were significantly higher in Italian than in the other study centers. Between the individual Italian centers, vasospasm accounted for the highest mortality rate in centers 7 and 8 (17% and 28% respectively). Postoperative pneumonia was significantly more frequent in Italian than in the other centers. In regard to timing of surgery, the differences in results between Italian and other centers were less marked when surgery was performed after 10 days from hemorrhage. In Italian centers as a whole, a delayed operation was linked with a better outcome than an early or subacute operation. The lowest recovery rate was observed in drowsy patients operated on between 4 and 10 days from the hemorrhage. Focal ischemic deficits and pneumonia were prevalent after an operation within 3 days of hemorrhage, while postoperative brain swelling was most frequent in patients operated on between 4 and 10 days from hemorrhage. The differences in results between Italian and other centers and among the individual Italian centers are widely discussed; possible explanations include inadequate modalities of treatment (especially inadequate management of vasospasm) and structural deficiencies of intensive care management in seriously ill patients.

The response of peripheral blood mononuclear cells of glioma-bearing patients to stimulation with microbial antigen and IL-2: proliferation and IFN-gamma production.

Peripheral blood mononuclear cells (PBMC) of malignant glioma-bearing patients were stimulated in vitro with a glucomannan-protein antigen of Candida albicans (GMP) or Interleukin-2 (IL-2), then assayed for proliferation and production of Interferon gamma. PBMC of healthy, age and sex matched subjects were the controls. PBMC from glioma-bearing patients did not differ, as a whole, from PBMC of healthy donors in IL-2 or GMP-induced proliferation. However, they showed a definitely lesser ability to produce IFN. The results are discussed in the framework of the impairment of immune responses known to affect glioma-bearing patients.

Low-dose tranexamic acid combined with aprotinin in the pre-operative management of ruptured intracranial aneurysms.

Among our patients with ruptured intracranial aneurysms 149 were managed pre-operatively with a combination of tranexamic acid (AMCA), 3 gm daily, and aprotinin at an average of 400,000 KIU (Kallikrein inactivating units) daily. Antifibrinolytics were started within three days of the last haemorrhage, and continued for at least six days. The first 91 cases, managed in the years 1971 to 1980, have been evaluated retrospectively. The remaining 58 patients were managed in the period 1981-1985 and carefully watched for possible complications of treatment. No significant differences were noted in the results of patients managed either before or after 1981. The rate of recurrent SAH (10%) was lower than the natural history of aneurysmal SAH. Satisfactory inhibition of fibrinolysis was documented in the CSF collected at the time of operation in 15 patients. This, as well as our previous suggestions that the combination of low-dose AMCA and aprotinin might carry a lesser risk of causing ischaemic complications and hydrocephalus than the conventional antifibrinolytic treatment, might stimulate future studies on fibrinolysis in SAH.

Neurophysiologic assessment of trigeminal function after surgery for trigeminal neuralgia.

To assess the function of the three trigeminal divisions, we studied corneal reflex, early and late blink reflexes, early and late masseter silent periods, and jaw jerk in normal subjects and in 35 patients submitted to surgery for trigeminal neuralgia. The corneal reflex was most sensitive to thermocoagulation and the jaw jerk to microcompression; the other reflexes showed an intermediate behavior, depending on afferent fiber size. Trigeminal function was less impaired after microcompression and recovered earlier than after thermocoagulation.

Immunocomplexes in rat and rabbit spinal cord after injury.

The possibility that, following a major lesion of the central nervous system, a humoral immune response could be evoked with formation of immune complexes "in situ" was investigated. For this purpose, an immunohistochemical study on rabbit and rat spinal cord at different times after surgical transection was carried out. The peroxidase-antiperoxidase method showed IgG decoration of the myelin sheaths starting a short time after surgery. The sera of intact and injured animals were then tested both by immunohistochemical methods on intact spinal cord sections and by immunoelectrophoresis on a protein extract of homologous spinal cord. The results showed in the rabbit the absence of antibodies to neural antigens before surgical injury and its appearance within a few days after surgery. On the other hand, in the rat, even before the injury, we found antibodies to neural tissue which decreased in the first few hours after injury, and returned to control values during successive days. The same experiments were conducted after a peripheral nerve lesion (sciatic nerve crush), but no immune response could be detected. The possible role of this immune response in the failure of axonal regeneration in mammalian spinal cord is briefly discussed.

Relationship between leukocytosis and ischemic complications following aneurysmal subarachnoid hemorrhage.

The prognostic significance of admission leukocytosis with respect to ischemic complications of subarachnoid hemorrhage was retrospectively investigated in a series of patients with recently ruptured intracranial aneurysms. The present study concerned 47 consecutive cases admitted within 72 hours following the last hemorrhage, in the years 1982-1984. There was no difference in the admission WBC counts between patients who subsequently deteriorated due to ischemic complications and those who did not. However, the cell count rose significantly at the time of the clinical manifestations of ischemia, possibly as a result of structural damage of brain tissue and/or increased sympathetic and adrenocortical activity. The possible contribution of leukocytes to the pathogenesis of ischemic damage following subarachnoid hemorrhage--perhaps through the release of leukotrienes--will require further investigation.

Pharmacokinetics of recombinant interferon-alpha 2 following intralesional administration in malignant glioma patients.

Pharmacokinetics of recombinant interferon-alpha 2 (rIFN-alpha 2) following intralesional administration into patients with malignant gliomas was investigated. A dose of 5 X 10(6) IU of rIFN-alpha 2 was injected locally postoperatively for 2 weeks each day, and the same dose was then given once a week for 10 additional weeks. During the daily and weekly administration, the IFN was consistently present in the fluid of the postsurgical cavity. Not until 5 weeks after the end of the IFN administration was the IFN undetectable. The decay of IFN injected was minimal.

Results of surgical management of 319 pituitary adenomas.

Of the 510 patients with pituitary adenoma treated surgically at our hospital in the period 1956-1984 319 were treated by the microsurgical technique, in the period 1973-1984, 235 by transsphenoidal approach and 84 by subfrontal-pterional approach. The transsphenoidal route was used almost exclusively in microadenomas, in intrasellar adenomas, in suprasellar adenomas with midline development, in adenomas invading the sphenoidal sinus and in haemorrhagic adenomas with considerable suprasellar development. In some giant adenomas the transsphenoidal route was used in a first stage operation for debulking the tumour, later removed by transcranial route. The latter route was preferred in large adenomas and especially in adenomas with laterosellar development. In some patients with PRL secreting adenomas post-operative treatment with bromocriptine proved useful when the hormone levels failed to normalize. Post-operative radiotherapy was of value in invasive adenomas and in cases in which tumour removal was not radical.