Induction of apoptosis in non-small lung carcinoma cell line (H1299) by combination of anti-asthma drugs with gemcitabine and cisplatin.

Gemcitabine and cisplatin are commonly used in chemotherapy, however, these drugs may cause severe cytotoxic side effects. Theophylline and aminophylline are commonly used as anti-asthma drugs and can block anti-phosphodiesterase activity. We examined whether these methylxanthins could effect lung cancer cell survival and synergise with gemcitabine and cisplatin to induce apoptosis. We found that theophylline induced apoptosis in the cultured H1299 cell line already at concentrations of 30 microg/ml, reaching an ED50% at 100 microg/ml. In contrast, aminophylline induced apoptosis at concentrations of 300 microg/ml and 17% apoptosis was evident at concentrations as high as 900 microg/ml, which is a lethal dose for in vivo treatment. Cisplatin induced apoptosis with ED50% of 0.8 microg/ml, while gemcitabine induced apoptosis with ED50% of 20 ng/ml. Using a combination of 20 microg/ml of theophylline (calculated as an effective but not toxic anti-asthma drug) with 10 ng/ml gemcitabine or with 0.3 microg/ml cisplatin significantly elevated incidence of apoptosis compared to gemcitabine or cisplatin alone at similar concentrations. In contrast, an observed synergistic effect between aminophylline and gemcitabine was evident only at concentrations of 80 microg/ml and 10 ng/ml respectively. However, no effect was apparent in combination doses of aminophylline (80 microg/ml) with cisplatin (0.3 microg/ml). The combined treatments involved reduction in the intracellular level of the anti-apoptotic Bcl-2 gene product. This corresponded with the extent of apoptosis induced by the various drug combinations. Thus, theophylline is significantly more effective than aminophylline in increasing the sensitivity of the H1299 lung cancer cells to the induction of cell death by gemcitabine and cisplatin. Thus, combination of theophylline with these drugs may permit a reduction in the effective dose needed in chemotherapy treatment of lung cancer patients.

Apoptosis in cryopreserved human ovarian tissue obtained from cancer patients: a tool for evaluating cryopreservation utility.

Fertility preservation is of major importance for women with cancer in whom ovarian function may be disturbed by the use of potentially sterilizing chemotherapeutic drugs and/or pelvic irradiation. Cryopreservation of ovarian cortical tissue is one of the potential options for preserving fertility among these women. Cryopreserved thawed human ovarian tissue can be autografted either orthotopically or heterotopically, but may also be transplanted first into an animal host with subsequent maturation and collection of oocytes. The objective of this study was to investigate the prevalence of ovarian follicular apoptosis in fresh and frozen/ thawed human ovarian tissue as a measure of follicular viability. The study group included 6 women with cancer who underwent ovarian tissue cryopreservation (OTCP). Ovarian tissue samples (n = 2) were obtained from each woman with one sample undergoing evaluation for apoptosis immediately following removal (control, group A) and the other evaluated for apoptosis following freezing/thawing (group B). Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) and 4'6' diamido-2-phenylindole hydrochloride (DAPI) staining methods were used to investigate follicular apoptosis. Morphological changes in the same samples were evaluated in hematoxylin and eosin (H&E)-stained sections. In each slide, only primordial and primary follicles were evaluated for abnormal morphology and apoptosis. Abnormal morphology was demonstrated in 23.8+/-8.7% of group A follicles compared to 48.3+/-11.2% of group B follicles (p < 0.05). Apoptosis was demonstrated in 25.4+/-8.4% of group A follicles compared to 60.9+/-6.0% of group B follicles (p < 0.05). We have shown that the ovarian follicles in group B demonstrated a higher incidence of apoptosis compared to those of group A. Therefore, the data suggest that follicular apoptosis might be a consequence of the freezing and thawing procedure. This may be used as a method for evaluating and comparing the outcome of different freezing/thawing protocols.

Arthroscopic electrothermal collagen shrinkage for symptomatic laxity of the scapholunate interosseous ligament.

The medical records, radiographs and operative reports of ten consecutive patients of average age 37 (range 19-67) years with wrist pain secondary to structural disruption of the scapholunate interosseous ligament (Geissler Type 2 injuries) who were treated with wrist arthroscopy and electrothermal collagen shrinkage of the scapholunate interosseous ligament were reviewed. Functional outcomes were assessed using the DASH scoring system at an average follow-up of 28 (range 12-44) months. At latest follow-up, nine patients (90%) were asymptomatic and had returned to their pre-injury functional level. The mean score on the DASH questionnaire was 20 (range 11-48). One patient developed wrist discomfort and mechanical symptoms 7 months postoperatively and required revision surgery. Our preliminary findings suggest that this may be a viable treatment option in the management of patients with symptomatic scapholunate interosseous ligament laxity without complete ligament disruption. Additional study is needed to better understand the role of this treatment modality.

Dehydroepiandrosterone Attenuates Cocaine-Seeking Behaviour Independently of Corticosterone Fluctuations.

The neurosteroid dehydroepiandrosterone (DHEA) is involved in the pathophysiology of several psychiatric disorders, including cocaine addiction. We have previously shown that DHEA attenuates cocaine-seeking behaviour, and also that DHEA decreases corticosterone (CORT) levels in plasma and the prefrontal cortex. Previous studies have found that rats demonstrate cocaine-seeking behaviour only when the level of CORT reaches a minimum threshold. In the present study, we investigated whether the attenuating effect of DHEA on cocaine seeking is a result of it reducing CORT levels rather than a result of any unique neurosteroid properties. Rats received either daily DHEA injections (2 mg/kg, i.p.) alone, daily DHEA (2 mg/kg, i.p.) with CORT infusion (to maintain stable basal levels of CORT; 15 mg/kg, s.c.) or vehicle (i.p.) as control, throughout self-administration training and extinction sessions. We found that both DHEA-treated and DHEA + CORT-treated groups showed a significantly lower number of active lever presses compared to controls throughout training and extinction sessions, as well as at cocaine-primed reinstatement. DHEA-treated rats showed lower CORT levels throughout the experimental phases compared to DHEA + CORT-treated and control rats. Additionally, we show that DHEA administered to cocaine-trained rats throughout extinction sessions, or immediately before reinstatement, attenuated cocaine seeking. These findings indicate that DHEA attenuates cocaine-seeking behaviour independently of fluctuations in CORT levels.

Unusual cause of relapsing hydrocephalus. Congenital intracranial teratoma.

We add clinical and pathological details of one male and one female infant with congenital pineal teratomas who died before reaching 3 months of age to the small number in the world literature. Each had a nonresectable, enormous neoplasm at the time of diagnosis, and shunting procedures were of no significant value. The pathological features of the tumors conformed in all respects to those classically described as true teratomas. An epidermal cyst, possibly metastatic, was found in the spinal subarachnoid space in one patient. There is currently no effective therapy for these neoplasms, although both were diagnosed during life. Whenever recurrent shunt insufficiency occurs in a hydrocephalic neonate, the possibility of a congenital brain tumor should be considered.

Drug development for ovarian hyper-stimulation and anti-cancer treatment: blocking of gonadotropin signaling for epiregulin and amphiregulin biosynthesis.

Gonadotropins play a crucial role in ovarian homeostasis and fertilization through the activation of the cAMP cascade. However, gonadotropin hyper-stimulation may be associated with higher risk for ovarian cancer development. It has been suggested, that high gonadotropin levels in peritoneal and ovarian cystic fluids of patients suffering from benign ovarian cysts, may lead to malignancy. Moreover, we have recently discovered that gonadotropin stimulation can activate the MAPK cascade in target cells. Using DNA microarray technology and RNA from human granulosa cells, we discovered that stimulation with saturating doses of gonadotropins dramatically elevates activity of genes coding for epiregulin and amphiregulin. These gene products can bind and activate the EGF receptor and ERBB4, which are associated with the development of various cancers such as ovarian, breast endometrial and other non-gynecological malignancies. Gonadotropin receptors are expressed not only in the gonads, but also in non-gonadal tissues and in cancer cells. The discovery that gonadotropins activate certain mitogenic signal transduction pathways, may serve as a guide for novel anti-cancer therapy by (1) specific interference at the receptor level to block the gonadotropic response, or arresting the receptor expression and (2) blocking downstream mitogenic signals generated by these hormones, like attenuation of the expression of epiregulin and amphiregulin that belong to the EGF family, using anti-sense and/or SiRNA techniques targeted to suppress their expression. Moreover, since amphiregulin and epiregulin act as mediators of luteinizing hormone (LH) action in the mammalian ovulatory follicles, regulation of the expression of these factors may open new possibilities in treatment of ovarian malfunction implicated with ovarian hyper-stimulation.

Alternative pathways of ovarian apoptosis: death for life.

Ovarian cell death is an essential process for the homeostasis of ovarian function in human and other mammalian species. It ensures the selection of the dominant follicle and the demise of excess follicles. In turn, this process minimizes the possibility of multiple embryo development during pregnancy and assures the development of few, but healthy embryos. Degeneration of the old corpora lutea in each estrus/menstrual cycle by programmed cell death is essential for maintaining the normal cyclicity of ovarian steroidogenesis. Although there are multiple pathways that can determine cell death or survival, crosstalk among endocrine, paracrine and autocrine factors, as well as among protooncogenes, tumor suppressor genes, survival genes and death genes, play an important role in determining the fate of ovarian somatic and germ cells. The establishment of immortalized rat and human steroidogenic granulosa cell lines and the investigation of pure populations of primary granulosa cells allows for systematic studies of the mechanisms that control steroidogenesis and apoptosis of granulosa cells. We have discovered that during initial stages of granulosa cell apoptosis progesterone production does not decrease. In contrast, we found that it is elevated for up to 24hr following the onset of the apoptotic stimuli exerted by starvation, cAMP, p53 or tumor necrosis factor alpha stimulation, before total cell collapse. These observations raise the possibility for an alternative unique apoptotic pathway, one that does not involve mitochondrial cytochrome C release associated with the destruction of mitochondrial structure and steroidogenic function. Using mRNA from apoptotic cells and Affymetrix DNA microarray we discovered that Granzyme B, a protease that normally resides in T cytotoxic lymphocytes and natural killer cells of the immune system is expressed and activated in granulosa cells, thereby allowing the apoptotic signals to bypass mitochondrial signals for apoptosis, which can preserve their steroidogenic activity until complete cell destruction. This unique apoptotic pathway assures the cyclicity of estradiol and progesterone release in the estrus/menstrus cycle even during the initial stage of apoptosis.

Chronic epidural hematomas.

Epidural hematomas generally become manifested within hours after trauma because of progressive obtundation and later transtentorial herniation. However, epidural hematomas located outside the temporal fossa may produce vague neurological symptoms of delayed onset. Emergency operation may not adequately expose those blood clots located in unexpected positions. Computed tomographic (CT) brain scans will reveal the full extent and location of these hematomas. Seven cases of chronic epidural hematoma in various extratemporal locations are reported to emphasize their misleading clinical courses, their demonstration by CT scanning, and the underlying pathophysiology.

Delayed traumatic intracerebral hematomas after surgical decompression.

Delayed traumatic intracerebral hematomas found after an initially unrevealing computerized tomographic scan have been reported occasionally. Such hemorrhage may occur in an area of brain contusion with cerebral vessel injury. Four cases of intracerebral hematoma appearing after evacuation of a different traumatic intracranial mass lesion are reported. This suggests that an intracranial mass lesion may tamponade cerebral venous oozing in an area of brain contusion and delay the accumulation of intracerebral blood, accounting for the late discovery of a parenchymal hematoma. (Neurosurgery, 5: 653--655, 1979).

Primary spinal chondrosarcoma with eighteen-year follow-up: case report and literature review.

Although chrondrosarcomas are common primary bone tumors, their occurrence in the spine is very rare. Because total excision in such cases is seldom possible, few long term survivors have been reported. We are reporting one patient with a high thoracic spinal chondrosarcoma who survived with useful function for over 18 years because of repeated local tumor excisions. The literature is reviewed, and an aggressive surgical treatment of spinal chondrosarcoma is recommended.

Sudden loss of pain control with morphine pump due to catheter migration.

The use of implantable morphine pumps for the treatment of cancer pain is increasing. A sudden loss of previously adequate pain control should suggest pump malfunction. Pump revision should be considered, rather than automatically increasing oral analgesics. This case report details a rapid loss of pain control due to intraspinal catheter migration into the abdominal subcutaneous space.

Malignant fibrous histiocytoma in a recurrent thoracic chordoma: case report and literature review.

Malignant transformation in a recurrent chordoma in the thoracic region is extremely uncommon. One new case, as well as a review of spinal chordomas that have undergone malignant transformation, is reported. Such cases emphasize the importance of the aggressive initial surgical treatment of spinal tumors.

Chronic encapsulated intracerebral hematoma.

Intracerebral hematomas producing chronic neurological disability are reported rarely. Two cases of chronic intracerebral hematoma are described. Each case was associated with a thick, fibrous capsule found histologically to arise from an occult vascular malformation. When such encapsulation is discovered surgically, a vascular anomaly must be suspected.

Spinal subdural metastatic adenocarcinoma: case report and literature review.

Metastatic spinal cancer is common and usually involves the bony spine or the epidural space. We are reporting a case of breast carcinoma metastatic to the spinal subdural space, and we review the literature concerning this unusual metastatic site. Unlikely metastatic locations should be suspected whenever myelography in cancer patients with spinal cord signs is confusing.

Clinical clerkships in neurosurgery and neurology at United States medical schools.

The neurology and neurosurgery clinical clerkship experience (excluding lectures and conferences) of the students in U.S. allopathic medical schools during one of the academic years 1986 to 1987 or 1987 to 1988 was surveyed. Almost all schools have at least some students taking these clerkships. The majority of students (78%) have clinical exposure to neurology, but only a minority (28%) take a neurosurgical clerkship; however, far more schools require their students to take neurology clerkships (54%) than neurosurgical clerkships (12%). A few require that either be taken. Overall, 81% of schools require all students to take at least one of these clerkships. For the most part, students taking a clerkship in either specialty do not do so again. The initial and usually unique exposure averages 3.5 weeks in neurology and 2.4 weeks in neurosurgery. For each specialty, required clerkships tended to be shorter than selective clerkships, which in turn were shorter than elective ones. Furthermore, first clerkships offered in the fourth year, whether they were required, selective, or elective, tended to be longer than the corresponding third-year first clerkships at other schools. Whereas the average length of a first clinical clerkship in neurology is almost as long for schools requiring it (3.4 wk) as for those that offer it as an elective or selective (4.0 wk), required neurosurgical clerkships are much shorter (1.5 wk) than elective or selective rotations (3.1 wk). Schools with residency training programs more frequently required students to a clerkship and, consequently, had greater numbers of students taking a clerkship in the corresponding specialty.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetic polyradiculopathy simulating lumbar disc disease. Report of four cases.

Most clinicians are aware of the common neurological effects of endocrine disorders. However, involvement of the spinal nerve roots is a poorly recognized complication of diabetes mellitus. Such involvement can closely simulate more common spinal diseases and thus lead to inappropriate therapy. Four cases of diabetic polyradiculopathy simulating lumbar disc disease are reported, and this distinctive entity is reviewed.

Intradural sacral nerve root metastasis mimicking herniated disc. Case report.

Spinal tumors may mimic herniated discs but the neurological findings and radiographs usually indicate the correct diagnosis. A case of metastasis to the S-1 intradural nerve rootlets is reported, with symptoms closely simulating a herniated disc. The correct diagnosis could not be made preoperatively in spite of clinical suspicion of a tumor.

Isolated symptomatic cervical spinous process fracture requiring surgery. Case report.

Isolated cervical spinous process fractures are common, but are usually considered to be inconsequential. Although such fractures may produce pain, complete recovery without residual symptoms is expected after conservative treatment, and neurological injury does not usually occur. The case of a patient with a persistently symptomatic C-2 spinous process fracture that required surgical treatment for pain relief is reported. A review of the pertinent literature illustrates with unusual clarity the interactions of social, political, and economic forces associated with this medical condition.

Nasal glioma.

Six cases of nasal gliomas, which are rare ectopic rests of neural tissue found at the root of the nose, are presented. It is important to distinguish nasal tumors from basofrontal encephaloceles to avoid inadvertent exposure of the brain during the surgical removal of mass lesions. Because of their related embryologic origins, the distinction between nasal gliomas and basofrontal encephaloceles may not be clear clinically. Nasal gliomas may be treated by several surgical specialties, and only a proper awareness of their relatonship to encephaloceles can assure the selection of a flexible and adequate surgical approach. This paper emphasizes the salient clinical characteristics of nasal gliomas, their clinical distinction form and embryologic relationship to encephaloceles, and the options for treatment.

Induction of polycystic ovary by testosterone in immature female rats: Modulation of apoptosis and attenuation of glucose/insulin ratio.

Polycystic ovarian syndrome is seen in 5% of fertile aged women. However, there is no satisfactory PCOS model in experimental animals. To induce polycystic ovary phenotype in immature female rats, Wistar rats 21 days of age were injected daily with testosterone propionate 1 mg/100 g body weight dissolved in propylene glycol or propylene glycol for up to 35 days. Seven days of injection with testosterone (T) resulted in the appearance of large cystic follicles and a dramatic accumulation of multi-layer preantral follicles. At 42 days of age puberty in control animals was evident by the appearance of corpora lutea. In contrast in T treated animals no corpora lutea formation was seen even at the age of 56 days. Progesterone in the control animals was elevated at the age of 42 days in contrast with the T treated animals in which progesterone remained low (20% of control). While during 14 days of T injection most of the follicles did not have progressive apoptosis, at 21-35 days of injection (42-56 days of age) the vast majority of follicles became apoptotic. Progressive degeneration of oocytes was evident in T treated animals reaching 70-85% of total oocytes at 21-35 days of T injection compared to 30-40% in control animals. Western blot analysis of ovarian homogenates revealed gradual decrease in Bcl-2 content, evident at 28 and 35 days of T injection compared to control animals. Interestingly, the fasting glucose/insulin ratio was dramatically reduced in T treated animals following 14 days of testosterone treatment compared to controls. Our data suggest that T injection to immature female rats can induce polycystic ovaries, block ovulation and attenuate progesterone production. Moreover, normal/low glucose and high insulin blood levels in the testosterone treated rats raises the possibility that elevated androgens can lead to insulin resistance in this experimental PCOS model.