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.

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.

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.

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.

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.

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.

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.

Nurse-midwifery at Gundersen Clinic: a twenty year review.

The twenty-year experience of the Certified Nurse-Midwife (CNM) Service at Gundersen Lutheran Medical Center is presented. The Service was started in September, 1975. From 1975 through 1995, the nurse-midwives have attended 9,120 women in labor (32.5% of all laboring women at Lutheran Hospital). During this time, the CNM service perinatal mortality rate was 6.8 per 1,000 births and the primary cesarean section rate was 5.8%. A close working relationship between nurse-midwives and obstetricians is thought to be one of the main factors in the growth, acceptance and safety of the service.

Disassembly of a modular humeral prosthesis. A case report.

A modular humeral hemiarthroplasty utilizing a prosthesis with a taper-lock design was performed on a 77-year-old woman with a diagnosis of rotator cuff arthropathy. Radiographic examination at 3 months after surgery revealed disarticulation of the modular head and neck from the humeral prosthetic stem. This is a case report of a disarticulated modular humeral hemiarthroplasty.

Thoracic spinal cord injury without spine fracture in an adult: case report and literature review.

The syndrome of traumatic spinal cord injury without spinal column fracture is well known and predominantly involves the cervical spine of children. One case of a thoracic spinal cord injury without bony abnormalities in an adult is reported, and the pertinent literature is reviewed. Although spinal cord injury without radiographic abnormality may exist, such injuries without neuroimaging pathology may not.

The synovial response after CO2 laser arthroscopy of the knee.

The CO2 laser is a precision surgical laser because of its high degree of absorption in soft tissue with limited lateral damage. The tissue, which absorbs the CO2 laser energy, and has a high water content, will be converted to vapor with a small residue of ash and a by-product of heat. The laser can only be effective if these by-products, i.e. vapors, heat, and carbon ash residue, are not injurious and are well tolerated by the joint. These by-products must be either reabsorbed by the synovium or remain as a nonviable substance in the joint. From April 1989 through April 1990, 40 patients underwent 43 operative arthroscopies of the knee using the Pfizer CO2 laser. All procedures were chondroplasties, synovectomies, and/or meniscectomies. All accessible CO2 carbon ash residue was removed from the joint after the procedures using an intraarticular shaver and hand rasp. Postoperatively there were no cases of hemorrhagic effusions, subcutaneous emphysema, or synovitis. Histologic examinations performed on 10 patients undergoing subsequent surgery showed no evidence of carbon ash residue or synovitis seen grossly or microscopically. The carbon ash residue is not noxious to the joint and is completely removed from the joint, presumably by the synovial response.

Unicompartment arthroplasty for osteoarthrosis of the knee.

Sixty-eight consecutive unicompartment knee arthroplasties were reviewed. Seven patients were lost to follow-up evaluation, and the review group consisted of 55 patients with 61 medial compartment replacements. Follow-up periods averaged 51 months, with a range of 24 to 70 months. All of the knees had a Robert Brigham unicompartment arthroplasty. All patients were evaluated using The Knee Society Clinical Rating System. Overall results revealed that 70% (42 patients) rated excellent, 10% (seven patients) rated good, 10% (six patients) rated fair, and 10% (six patients) were failures. Preoperative scores in the pain, range of motion, and stability sections averaged 54 points of a maximum of 100. Postoperatively, the scores averaged 87 points. Postoperative roentgenographs were evaluated using The Knee Society Roentgenographic Evaluation and Scoring System. Roentgenographs revealed at least one radiolucent line in 16 femoral components and 15 tibial components, and nine in both. Four of the six failures in the series had lucent lines in both the femur and tibia. This procedure is recommended in active patients between the ages of 55 to 65 years with single compartment disease. Also, a unicompartment arthroplasty is recommended in more sedentary patients 65 years and older with single compartment disease.

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)

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.

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.

The results of operative treatment of osteochondritis dissecans of the patella.

The course of osteochondritis dissecans (OCD) of the patella and the results of operative treatment are analyzed retrospectively in a review of 31 operatively treated cases in 25 patients. Followup was obtained for 21 cases, with an average of 73 months (range, 15 months to 20 years). These 25 patients were predominantly males, and averaged 18 years of age at the time of surgery. A history of trauma was associated with the lesion in 38% of the cases, and the lesion was bilateral in one out of four patients. The most common presenting complaints were subpatellar pain and swelling. The most common initial physical findings were patellofemoral crepitus and joint effusion. Forty-four operations were performed on 31 knees. The most commonly performed procedures were curettage of the patella and removal of loose bodies, in combination or as part of another procedure. A new patellofemoral rating scale was used to evaluate results. Thirty-eight percent of the knees had a good or excellent result, while 62% had a fair or poor result. Persistent pain with restricted function and residual patellofemoral crepitus were common findings. In general, the patients who come to surgery for OCD of the patella have a guarded prognosis for full recovery of knee function.

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.

Carpal tunnel syndrome. Avoiding poor treatment results.

Carpal tunnel syndrome is one of the most common causes of paresthesias, pain, and weakness of the hands. All physicians should be aware of the typical presentation of the syndrome, its differential diagnosis, and the various options for treatment. The prognosis with surgical treatment is excellent if significant muscle atrophy has not occurred.