A computational bioinformatics analysis of gene expression identifies candidate agents for prostate cancer.

Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males worldwide. Although great progress has been made, the molecular mechanisms of prostate cancer are far from being fully understood and treatment of this disease remains palliative. In this study, we sought to explore the molecular mechanism of prostate cancer and then identify biologically active small molecules capable of targeting prostate cancer using a computational bioinformatics analysis of gene expression. A total of 3068 genes, involved in cell communication, development, localisation and cell proliferation, were differentially expressed in prostate cancer samples compared with normal controls. Pathways associated with signal transduction, immune response and tumorigenesis were dysfunctional. Further, we identified a group of small molecules capable of reversing prostate cancer. These candidate agents may provide the groundwork for a combination therapy approach for prostate cancer. However, further evaluation for their potential use in the treatment of prostate cancer is still needed.

Ultrasonographic evaluation of splenic enlargement in athletes with acute infectious mononucleosis.

OBJECTIVE: To quantitatively assess the degree and rate of splenic enlargement and the time required for regression of splenic enlargement in collegiate athletes diagnosed with acute infectious mononucleosis (IM). DESIGN: Prospective cohort study. SETTING: Academic Medical Center(s) outpatient sports medicine clinic. STUDY PARTICIPANTS: Volunteer Division I University athletes. INTERVENTIONS: A limited abdominal ultrasound was performed on each participant by a licensed and experienced ultrasonographer. Splenic measurements were taken to assess maximum splenic length. Athletes who were subsequently diagnosed with infectious mononucleosis (clinical illness and a positive monospot) underwent serial splenic ultrasounds and physical exams (weekly) until resolution of clinical symptoms and splenic enlargement (as determined by ultrasound measurements). MAIN OUTCOME MEASURES: Per cent enlargement of spleen size (length) from baseline. Time (in days) from onset of clinical illness to maximum splenic length. Time (in days) required for resolution of splenic enlargement. RESULTS: 20 subjects were diagnosed with acute IM during a 5 year time period. Maximum splenic length increased a mean of 33.6% (SD 19.9%) from baseline values. Peak splenic enlargement was reached a mean of 12.3 (SD 5.1) days from onset of clinical illness. A linear model demonstrated that spleen size decreases approximately 1% per day after reaching peak splenic enlargement. CONCLUSIONS: The majority of athletes with IM experience a moderate degree of splenomegaly. Peak splenic enlargement occurs within 2 weeks from the time of symptom onset in most cases, but may extend to 3.5 weeks. The rate of splenic enlargement appears to be predictable for an individual who develops IM. Ultrasonographic data further show that splenomegaly associated with acute IM infection resolves within 4-6 weeks of symptom onset in the majority of cases.

Intra-articular hyaluronic acid injections for knee osteoarthritis.

Knee osteoarthritis is a common but often difficult problem to manage in primary care. Traditional nonsurgical management, consisting of lifestyle modification, physical therapy and pharmacologic therapy (e.g., analgesics, anti-inflammatory medications), is often ineffective or leaves residual symptoms. Viscosupplementation is a newly available option for patients with symptomatic knee osteoarthritis that involves a series of intra-articular injections of hyaluronic acid. The exact mechanism of action is unclear, although increasing the viscoelasticity of the synovial fluid appears to play a role. Clinical experience and studies of the two hyaluronic acid products available, hyaluronan and hylan G-F 20, are inconclusive but seem to indicate beneficial effects with minimal adverse reactions in a significant number of patients. The exact indications for viscosupplementation are still evolving, but it currently can be considered for use in patients who have significant residual symptoms despite traditional nonpharmacologic and pharmacologic treatments. In addition, patients who are intolerant of traditional treatments (e.g., gastrointestinal problems related to anti-inflammatory medications) can be considered for these injections. Family physicians with the ability to perform intra-articular knee injections should consider them an option in patients with symptomatic knee osteoarthritis.

Current concepts in the treatment of anterior shoulder dislocations.

Anterior shoulder dislocations are commonly seen in emergency departments. With the recent proliferation of shoulder arthroscopy, the pathoanatomy has been better delineated. Arthroscopic series have confirmed the very high percentage of Bankart lesions (avulsions of the inferior glenohumeral ligament-labral complex), especially in younger patients. A high rate of recurrent dislocation in young patients has been noted in the literature with standard conservative treatment, consisting of immobilization with or without rehabilitation. This high recurrence rate is thought to be due to the Bankart lesion. Recently, investigations with the use of arthroscopic Bankart repairs have shown high success rates in preventing recurrences, with low surgical morbidity. A young, first-time, traumatic anterior dislocation patient should be referred for consideration of possible early arthroscopic Bankart repair, rather than automatically being treated conservatively with immobilization.

Complications of subcutaneous low-dose heparin therapy in neurosurgical patients.

BACKGROUND: Venous thromboembolism is a major cause of postoperative morbidity and mortality in neurosurgery. The use of low-dose unfractionated heparin therapy perioperatively for prophylaxis against deep vein thromboses and pulmonary embolism has been well demonstrated in many other surgical specialties but is less commonly used in neurosurgery because of fears of devastating postoperative hematomas. METHODS: The safety of such therapy has been analyzed in 950 patients undergoing an inpatient neurosurgical procedure. 872 patients (152 cranial procedures) completed treatment with 5000 U sodium heparin subcutaneously twice a day, commencing before surgery and continuing till patients were ambulatory. RESULTS: There were three minor hemorrhagic complications-two superficial wound hematomas (one requiring treatment) and one gastrointestinal hemorrhage-identified. Three clinically significant major complications developed, two epidural hematomas after spinal surgery requiring evacuation and one intraventricular hemorrhage after brain biopsy. CONCLUSION: This report, along with an analysis of previously published reports of low-dose perioperative heparin therapy in neurosurgical patients, suggests that such therapy is unlikely to be associated with increased morbidity. Given the known efficacy of low-dose heparin in reducing venous thromboembolism in other surgical patients, such therapy may reduce mortality and morbidity from thromboembolic complications in neurosurgical patients with minimal risk.

Injuries in runners: a prospective study of alignment.

OBJECTIVE: To determine if measurable lower extremity alignment is a risk factor for overuse running injuries. DESIGN: Prospective cohort study. SETTING: Thirty-two week marathon training program. PATIENTS OR PARTICIPANTS: Three hundred fifty-five volunteers from the marathon training program began the study; 255 finished the study. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Past training and injury history was determined by questionnaire, and five lower extremity alignment measures were performed at the beginning of the training program: arch index (AI), heel valgus (HV), knee tubercle-sulcus angle (TSA), knee varus (KV), and leg-length difference (LLD). Overuse injuries, incurred by the runners and categorized by anatomic parts, were recorded during the training period. RESULTS: Ninety subjects experienced overuse injuries. Multivariate analyses with stepwise Poisson regression showed few consistent relationships between alignment and overuse injury rates. Higher AI was protective against overall injuries and knee injuries; higher HV was protective against knee and foot injuries; higher TSA was associated with shin injuries; higher KV was associated with shin injuries; and low LLD was associated with more overall injuries. CONCLUSIONS: Minor variations in lower extremity alignment do not appear conclusively to be major risk factors for overuse injuries in runners. Because of the study limitations and the likely multifactorial nature of running injuries, further study is suggested, perhaps in more novice runners.

Lower extremity alignment and risk of overuse injuries in runners.

A group of 304 runners enrolling in a marathon training program had alignment measurements performed and completed a questionnaire on training practices and injuries over the previous 12 months. The alignment measures consisted of arch index (AI), heel valgus (HV), knee tubercle-sulcus angle (TSA), knee varus (KV), and leg-length difference (LLD). Results indicated few consistent statistical associations between these alignment measures and risk of injuries, either bivariately or multivariately: left AI with hamstring injuries; right AI with shin injuries; right HV with back injuries; left TSA with ankle injuries; KV with hip injuries; and LLD with back, ankle, and foot injuries. A few statistically significant relationships were also found between other training and anthropometric factors and injuries: mileage with hamstring injuries; interval training with shin injuries; hard surfaces with back and thigh injuries; shoe use patterns with foot and overall injuries; and body mass index with heel injuries. We conclude that lower-extremity alignment is not a major risk factor for running injuries in our relatively low mileage cohort; however, prospective studies are necessary to confirm or refute these findings.

Intracranial aneurysm rupture presenting as delayed stroke secondary to cerebral vasospasm.

BACKGROUND: Days after aneurysmal subarachnoid hemorrhage (SAH), cerebral vasospasm can result in the delayed appearance of ischemic neurological deficit identical to that produced by other causes of stroke. Despite the well-described, "classic" presentation of SAH, up to 25% of patients are initially misdiagnosed, and the initial hemorrhage from a ruptured aneurysm will not always bring the patient to medical attention. CASE DESCRIPTIONS: We report our experience with two patients who presented with signs and symptoms of ischemic stroke resulting from cerebral vasospasm that followed unrecognized rupture of a brain aneurysm. In one case, it was the recent complaint of significant headache and a prior history of SAH that led to the correct diagnosis. In the other case, a major rebleed occurred before the accurate diagnosis was recognized. CONCLUSIONS: It is critical to make the correct diagnosis of stroke due to vasospasm so that appropriate treatment can be instituted, thrombolytic and anticoagulant therapy can be avoided, and the unsecured aneurysm can be obliterated to prevent potentially catastrophic rebleeding.

Platelet receptors for the Streptococcus sanguis adhesin and aggregation-associated antigens are distinguished by anti-idiotypical monoclonal antibodies.

Platelets aggregate in response to an adhesin and the platelet aggregation-associated protein (PAAP) expressed on the cell surfaces of certain strains of Streptococcus sanguis. We sought to identify the corresponding PAAP receptor and accessory adhesin binding sites on platelets. Since the adhesion(s) of S. sanguis for platelets has not been characterized, an anti-idiotype (anti-id) murine monoclonal antibody (MAb2) strategy was developed. First, MAb1s that distinguished the adhesin and PAAP antigens on the surface of S. sanguis I 133-79 were selected. Fab fragments of MAb1.2 (immunoglobulin G2b [IgG2b]; 70 pmol) reacted with 5 x 10(7) cells of S. sanguis to completely inhibit the aggregation of human platelets in plasma. Under similar conditions, MAb1.1 (IgG1) inhibited the adhesion of S. sanguis cells to platelets by a maximum of 34%, with a comparatively small effect on platelet aggregation. Together, these two MAb1s inhibited S. sanguis-platelet adhesion by 63%. In Western immunoblots, both MAb1s reacted with S. sanguis 133-79 87- and 150-kDa surface proteins and MAb1.2 also reacted with purified type I collagen. The hybridomas producing MAb1.1 and MAb1.2 were then injected into BALB/c mice. Enlarged spleens were harvested, and a panel of MAb2 hybridomas was prepared. To identify anti-ids against the specific MAb1s, the MAb2 panel was screened by enzyme-linked immunosorbent assay for reaction with rabbit polyclonal IgG antibodies against the 87- and 150-kDa antigens. The reactions between the specific rabbit antibodies and anti-ids were inhibited by the 87- and 150-kDa antigens. When preincubated with platelets, MAb2.1 (counterpart of MAb1.1) inhibited adhesion to platelets maximally by 46% and MAb2.2 (anti-MAb1.2) inhibited adhesion to platelets maximally by 35%. Together, both MAb2s inhibited the adhesion of S. sanguis to platelets by 81%. MAb2.2 also inhibited induction of platelet aggregation. MAb2.2 immunoprecipitated a biotinylated platelet membrane antigen of 170 kDa (unreduced); MAb2.1 precipitated membrane antigens of 175- and 230-kDa (unreduced). Therefore, platelet binding sites and the receptor for the S. sanguis adhesin and PAAP, respectively, are distinguished by the anti-id MAb2s.

Meningeal sarcoma mimicking an acute subdural hematoma on CT.

A case of meningeal sarcoma arising at the site of a prior subdural hematoma and mimicking an acute subdural hematoma on noncontrast CT is presented. The potential confusion between a hyperdense, nonhemorrhagic lesion and a hematoma on CT is highlighted. This report also reviews the possible relationship between meningeal injury and subsequent neoplastic change.

In vitro and in vivo variation in transferrin receptor expression on a human medulloblastoma cell line.

The poor prognosis associated with pediatric central nervous system tumors such as medulloblastoma has led to the development and investigation of a variety of new treatment techniques. Therapeutic agents include targeted-toxin conjugates or immunotoxins that show significant in vitro activity against many brain tumors. Transferrin receptors (TRs) are specific, cell-surface antigens that are expressed preferentially on brain tumors rather than on normal human brain tissue. This antigen has been successfully targeted in human and nonhuman brain tumors in vitro and in vivo. In this study, when TRs were used as a target in the DAOY human medulloblastoma-derived cell line in vitro, a significant level of expression was confirmed by testing the sensitivity to different immunotoxins. To ensure the relevance of the in vitro data to the in vivo situation, we also analyzed TR expression in DAOY tumors growing in athymic mice and rats. Immunocytochemistry, immunohistochemistry, immunobead binding, immunofluorescence, 125iodine-transferrin binding, and Northern blot analysis were used to compare TR expression in DAOY cells in vitro and in vivo. All in vitro assays demonstrated significant TR expression, whereas in vivo, the TR expression was negligible in the DAOY tissue. The results caution against extrapolating in vitro antigen and receptor expression data directly to the in vivo situation. Using a transferrin-toxin conjugate in a nude rat model of leptomeningeal carcinomatosis, we achieved therapeutic efficacy, despite demonstrating reduced TR expression on tumor tissue. With respect to clinical efficacy, the reduced expression of TR on DAOY medulloblastoma in vivo may be less significant than expected because of the extreme potency of immunotoxins observed in central nervous system tumors.

Rapid detection of transferrin receptor expression on glioma cell lines by using magnetic microspheres.

A rapid method for detecting the presence of transferrin receptors (TR) on human glioblastoma-derived cell lines is presented. The development of new treatment modalities, such as immunotoxins for central nervous system cancer, requires the identification of appropriate surface antigens on tumor cells. Seven established human glioblastoma-derived cell lines were assayed for the presence of TR with antibody-coated magnetic microspheres (immunobeads). The immunobeads bound to glioblastoma cells in the presence of human anti-TR monoclonal antibodies to a significantly greater degree than to control cell lines (P < 0.0001). The expression of TR was confirmed by standard immunocytochemical techniques. A 9L rat gliosarcoma cell line was used as a nonhuman control and did not demonstrate TR expression by either the immunobead assay or immunocytochemistry. This assay represents a simple, sensitive way to detect TR expression on malignant cells, which may be useful for the identification of other cell surface antigens that can be exploited by targeted therapies.

Surgical approaches to the brain stem.

During the last decade there has been a remarkable increase in the interest of neurosurgeons in surgical approaches along the base of the skull. A plethora of different approaches, most of which involve a slight variation of a previously described approach, have been reported in the recent literature, frequently with proprietary claims of originality. This increased confidence of the neurosurgeon in approaching lesions along the base is due to our renewed interest in the anatomy of the skull base and our willingness to collaborate with some of our colleagues in otorhinolaryngology who have concentrated their surgical anatomic studies in this area for years. It is clear that the neurosurgeon who currently undertakes surgery of complex lesions involving the base of the skull, the brain stem and the associated cranial nerves and arteries must have a thorough understanding of this anatomy and frequently must engage the help of an ear-nose-and-throat colleague to enhance his or her own expertise with these complex cases. The emerging principle is that whenever possible, exposure should be obtained through carefully planned bone removal along the base rather than through brain retraction. It needs to be emphasized, however, that most of the complex approaches alluded to in the preceding sections are necessary only when the surgeon is dealing with extrinsic lesions, neoplastic or vascular, that only secondarily affect the brain stem itself. Almost all intrinsic lesions of the brain stem can be accessed through one of the more traditional approaches with which all neurosurgeons should be fully familiarized. When the lesion involves or points toward the floor of the fourth ventricle, a standard suboccipital approach through the vermis suffices. Lesions presenting in the cerebellopontine angle or the lateral pons may be safely approached through a standard retromastoid craniectomy. A more direct (perpendicular) access can be obtained by a standard subtemporal-transtentorial approach when the lesion is high and lateral, by a combined subtemporal-suboccipital approach when the lesion extends more inferiorly, and by a combined subtemporal-presigmoid approach for the more anteriorly located lesions. Anterior or anterolateral lesions of the highest aspect of the pons or of the mesencephalon can be readily accessed by the pterional-anterior temporal approach or by a standard subtemporal approach. Dorsal mesencephalic lesions require a supracerebellar/infratentorial approach or, when they extend more inferiorly, an occipital transtentorial approach. When the ventral aspect of the lower brain stem is involved, the lateral suboccipital approach works well.(ABSTRACT TRUNCATED AT 400 WORDS)

Targeted brain biopsy: a comparison of freehand computed tomography-guided and stereotactic techniques.

With computed tomography (CT) and magnetic resonance imaging stereotactic systems, biopsies of intracranial lesions can be made with safety and ease. Before the development of this technique, neurosurgeons often performed freehand brain biopsies under CT guidance. While stereotactic biopsy is the procedure of choice for small, deep lesions, few studies have compared the morbidity, mortality, and efficacy in obtaining a diagnosis associated with these two techniques for superficial lesions. A total of 167 consecutive CT-guided or stereotactic brain biopsies were performed in 154 patients. Fourteen of the stereotactic and 12 of the CT-guided biopsies were of deep lesions and were excluded from analysis. The results of 75 freehand CT-guided biopsies of superficial lesions in 69 patients were compared with those of 66 stereotactic biopsies (34 CT-guided and 32 MRI-guided) performed with the Brown-Roberts-Wells stereotactic system in 60 patients. Twenty-five of the lesions in the stereotactic biopsy group measured < or = 2 cm, as compared with 13 of those in the freehand CT-guided biopsy group. There were no biopsy-related deaths among the patients who underwent freehand CT-guided biopsy and one death among those who underwent stereotactic biopsy (1.5%). Freehand CT-guided biopsy was associated with 5% morbidity, compared with 6% morbidity for stereotactic biopsy. Seven CT-guided needle biopsies (9%) and 12 stereotactic biopsies (18%) were nondiagnostic. Statistical analysis showed no significant difference between morbidity and mortality in the two groups, but the rate of diagnostic failure was significant (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Papilledema and intraspinal lumbar paraganglioma.

Optic nervehead swelling is most frequently caused by ocular or intracranial lesions. The case presented here demonstrates that the spinal subarachnoid space must also be considered as a potential site for a lesion causing optic nervehead swelling. A 56-year-old man is presented with an intraspinal lumbar paraganglioma associated with increased cerebrospinal fluid protein, papilledema, transient obscurations of vision, and back pain. This may be the first reported case of a paraganglioma associated with optic nervehead swelling. Magnetic resonance imaging of the lumbosacral region revealed the lesion noninvasively. The papilledema, transient obscurations of vision, and back pain resolved after resection of the tumor. The mechanisms are not defined for optic nervehead swelling in association with spinal tumors in general and paraganglioma in particular. The measured abnormal elevation of cerebrospinal fluid protein may have resulted in increased intracranial pressure and papilledema.

Infections in neurologic surgery. The intraventricular use of antibiotics.

Intraventricular antibiotic therapy appears to be a useful treatment modality in those CSF infections in which systemic therapy may fail. Consideration should be given to using this form of treatment when infecting organisms are only sensitive to antibiotics with poor penetration of the CSF (e.g., aminoglycosides and vancomycin) and for cases in which intravenous therapy has failed to sterilize the CSF, toxicity from systemic therapy precludes further increases in dosages, and shunts or other CSF hardware might be expected to reduce the efficacy of systemic therapy by providing a foreign body to harbor organisms. Shunts or reservoirs that are infected may be successfully sterilized with IVT therapy alone or in conjunction with systemic therapy, but this has a lower success rate than cases in which the shunt is removed. There is a wealth of clinical experience with IVT vancomycin and gentamicin that suggests that they are relatively safe. Until more data are available on other aminoglycosides and newer antibiotics, these two agents should be considered the antibiotics of choice for IVT therapy. In situations in which the organism is sensitive to both vancomycin and gentamicin, vancomycin should be used in view of the documented neurotoxicity seen with gentamicin. When gentamicin resistance occurs, amikacin and tobramycin are appropriate alternatives. The high risk of epilepsy with the penicillins and cephalosporins makes them less suited for IVT therapy, although the newer cephalosporins have some promise for IVT therapy. CNS fungal infections can be treated effectively with IVT amphotericin B but with a high risk of significant toxicity. Miconazole appears to be safer than amphotericin B but there is less clinical experience with this drug. Table 1 summarizes the dosages, indications, and toxicity of those antibiotics commonly used for intraventricular administration, which have been reported previously.

Microsurgical management of craniopharyngiomas.

A retrospective analysis of 34 patients who underwent microsurgical therapy for craniopharyngioma from 1975 to 1989, a period when CT imaging was routinely used, is presented. Mean follow-up was 6.4 years with no patients lost to follow-up. Those who underwent subtotal resection with adjuvant radiation had a significantly better recurrence-free interval compared with those who either underwent total or subtotal surgical resection only (p < 0.05 and p < 0.025). Among patients treated with surgery alone, the total resection group had a recurrence rate of 20% and those with a subtotal resection 60%. Those with subtotal resection and radiation had a 12% rate of recurrence. Endocrine and visual deficits were common after surgery. Based on this review, our results suggest that with a policy of attempted total resection where possible, subtotal removal along with adjuvant radiation, in cases where total resection was deemed unsafe, may be more effective than aggressive total resection alone as the initial management of craniopharyngioma.

Elevated intracranial pressure from cerebral venous obstruction by Masson's vegetant intravascular hemangioendothelioma. Case report.

The case is described of a 15-year-old girl with papilledema and visual obscurations caused by a rare lesion, Masson's vegetant intravascular hemangioendothelioma, within the venous sinus at the torcular herophili. This lesion impeded cranial venous outflow, leading to intracranial hypertension.

Acute cervical myelopathy from hereditary multiple exostoses: case report.

A case of hereditary multiple exostoses with acute cervical myelopathy, tetraplegia, and apnea is reported. Neurological complications as a result of osteochondromas in hereditary multiple exostoses are rare. The majority of osteochondromas in the cervical spine arise from the neural arch. Magnetic resonance imaging and computed tomography are invaluable in localizing the origin of the lesion and its relationship to the spinal cord. Decompressive laminectomy usually results in excellent functional recovery. Where significant dorsal spinal cord compression exists without neurological deficit, prophylactic decompression can be recommended.

Application of invasive microwave hyperthermia for the treatment of gliomas.

Twenty five cases of gliomas of the brain were operated upon by debulking the tumour masses. Following this, microwave hyperthermia was given by heating a measured volume of Ringer's solution instilled into the tumour cavity. This was followed by a 'dry treatment' without Ringer's solution. The follow up of these cases revealed that 11 cases have died and 14 cases are alive post-operatively. For those that are alive, the follow up period ranges from 21 to 41 months with the mean survival period of 31.1 months; in this group, 12 cases have a Kanofsky scale of 80-100, i.e. they are fully independent. The other two cases have a score of 50 or under and they need institutional care. In this study, we believe that the first order effect of microwave hyperthermia is predominantly thermal and in the published literature, and in this investigation, there is no clear evidence that microwave radiation produces any other beneficial and quantifiable effect on the tissue.