Preliminary study of a genetically engineered spinal cord implant on urinary bladder after experimental spinal cord injury in rats

The objective of this study was to determine the effect of neurotrophin-secreting Schwann cell implants on the urinary bladder after spinal cord contusion. One hour after severe spinal cord contusion at the T8 to T11 level, carbon filaments containing nonsecreting Schwann cells, brain-derived neurotrophic factor (BDNF)-secreting Schwann cells, neurotrophin-3 (NT-3)-secreting Schwann cells, or Schwann cells secreting both BDNF and NT-3 were implanted into the spinal cord. Untreated spinal cord injured (SCI) rats and noncontused rats (C) were also studied. Two months after spinal cord injury, cystometry was performed and the bladders were studied using light microscopy. SCI rats had significantly increased bladder mass, thickness, and smooth muscle mass compared to C rats. Bladder capacity of SCI rats and rats with spinal cord implants were both significantly greater than that of C rats. This preliminary study suggests that neurotrophin-secreting Schwann cell implants may lead to improved bladder structure after spinal cord injury.     

Self-poisonings with drugs by adolescents in the Lund catchment area

Our objective was to investigate which drugs young people who attempt suicide use in the Lund catchment area eight municipalities in Skåne, southern Sweden. All patients aged up to 18 years admitted to Lund University Hospital after deliberate or probably deliberate self-poisoning from 1 January 1991 until 31 December 1995 were included. Forty-nine (58%) had used a single drug; 20 (24%) had used 3 or more drugs. Fifty-two (61%) used analgesics paracetamol was used by 38 (45%) and propoxyphene by 17 (20%). Thirty-one (36%) had ingested psychotropics 13 used benzodiazepines, 10 antidepressants, and 8 antipsychotics. Eleven (15%) had used drugs in combination with alcohol. We conclude that it is important to follow changes in self-poisoning patterns, to monitor the effects of preventive work and discover new trends in drug use.     

Anti‐leukemic activity of valproic acid and imatinib mesylate on human Ph+ ALL and CML cells in vitro

The armamentarium of anti‐leukemic drugs has increased substantially since anti‐leukemic activities were recently found for a variety of non‐classical cytostatic drugs, among them the histone deacetylase (HDAC) inhibitor valproic acid (VPA). This study investigated the effect of VPA on proliferation and apoptosis of human Philadelphia chromosome‐positive (Ph+) acute lymphatic (ALL) and chronic myeloid leukemia (CML) cells and on colony formation of human chronic‐phase CML progenitor cells. Strong anti‐proliferative and pro‐apoptotic effects of VPA were observed on human ALL and CML cell lines at concentrations achievable in vivo. These effects were most pronounced in ALL cell lines as well as in primary ALL cells. Notably, VPA revealed enhanced activity with imatinib mesylate, nilotinib, the farnesyl transferase inhibitor SCH66336, interferon‐alpha and cytosine arabinoside. VPA inhibited the growth of colony‐forming cells from 12 Ph+ chronic‐phase CML patients but also of those from normal healthy controls in a dose‐dependent fashion. HDAC‐inhibiting activity of VPA was confirmed on ALL and CML cells. In conclusion, VPA, whether alone or in combination with other non‐classical anti‐leukemic compounds, exerts significant anti‐leukemic effects on human ALL and CML cells.     

TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model

Despite improvements in detection, surgical approaches and systemic therapies, breast cancer remains typically incurable once distant metastases occur. High expression of TRAIL-R2 was found to be associated with poor prognostic parameters in breast cancer patients, suggesting an oncogenic function of this receptor. In the present study, we aimed to determine the impact of TRAIL-R2 on breast cancer metastasis. Using an osteotropic variant of MDA-MB-231 breast cancer cells, we examine the effects of TRAIL-R2 knockdown in vitro and in vivo. Strikingly, in addition to the reduced levels of the proliferation-promoting factor HMGA2 and corresponding inhibition of cell proliferation, knockdown of TRAIL-R2 increased the levels of E-Cadherin and decreased migration. In vivo, these cells were strongly impaired in their ability to form bone metastases after intracardiac injection. Evaluating possible underlying mechanisms revealed a strong downregulation of CXCR4, the receptor for the chemokine SDF-1 important for homing of cancers cells to the bone. In accordance, cell migration towards SDF-1 was significantly impaired by TRAIL-R2 knockdown. Conversely, overexpression of TRAIL-R2 upregulated CXCR4 levels and enhanced SDF-1-directed migration. We therefore postulate that inhibition of TRAIL-R2 expression could represent a promising therapeutic strategy leading to an effective impairment of breast cancer cell capability to form skeletal metastases.     

Antitumoral activity of a sulphur-containing platinum complex with an acidic pH optimum

Platinum complexes are essential tools for cancer treatment despite their toxic side effects. Here we describe a new platinum complex with sulphurs as complexing atoms (thioplatin). PURPOSE: To demonstrate that the antitumoral activity of a new sulphur-containing platinum compound (thioplatin) depends on a slightly acidic pH. METHODS: Platinum uptake by tumour cells and interaction with DNA was determined at slightly acidic or alkaline pH. To demonstrate low in vivo toxicity the effects of thioplatin on body weight, blood urea nitrogen, white blood cell count and the histopathological appearance of small intestines and kidneys were evaluated at doses that displayed antitumoral effects against human small-cell lung cancer and human colorectal cancer xenotransplants in nude mice. RESULTS: The slightly acidic pH optimum of thioplatin was proven by the altered electrophoretic mobility of plasmid DNA, quantitation of the platinum content in the DNA of tumour cells and cytotoxicity studies. Thioplatin displayed antitumoral activity without severe side effects such as weight loss, renal ischaemia, destruction of villi in the small intestine or leukopenia as observed at comparable doses of cisplatin. Furthermore, probably due to its lipophilic nature, thioplatin was taken up readily even by cisplatin-resistant cells. In vivo studies with human tumour xenografts in nude mice showed a therapeutic index of thioplatin five to ten times higher than that of cisplatin.     

Risk Indicators: Assessment of Infancy Predictors of Pre-School Behavioural Maladjustment

The prediction of later outcome from factors present in infancy has been an ongoing concern, with difficult temperament frequently being posited as one important risk factor. Using data from a longitudinal study of a large representative sample of children, and a categorical approach to analysis, a set of infancy risk factors covering within-child, environmental and relationship variables was related to behavioural and emotional adjustment at 4-5 years. Single risk factors, including difficult temperament, resulted in only modest increases in the prevalence of later maladjustment. However, certain combinations of risk factors were associated with markedly increased prevalence rates. The results indicate the cumulative effects of risk factors, and the need to consider temperament within a contextual framework.     

Pathogenesis of small-intestinal mucosal lesions in chronic diarrhea of infancy: I. A light microscopic study

In an effort to increase our understanding of the pathogenesis of chronic protracted diarrhea in infants, we examined 44 jejunal mucosal specimens. Only 3 of the 44 specimens showed a normal mucosa (grade 1). Partial villous atrophy was seen in 17 mucosal specimens (grade 2) with marked patchiness in all of the specimens. Subtotal or total villous atrophy (grade 3) was found in the remaining 24 mucosal biopsies. Plasma cells and macrophages were variably increased and intraepithelial lymphocytes were moderately increased in grades 2 and 3. Eight of ten mucosal biopsy specimens embedded in plastic material and cut at 1-2-mm thickness, showed bacteria of unidentified nature, situated either above the microvillous layer or on the mucosal surface. Both adherent and nonadherent bacteria could be identified in the same specimen. We concluded that severe pathological mucosal changes are common in young infants with protracted diarrhea and that the presence of bacteria may be more common than has previously been documented.