Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats

Estradiol benzoate (EB) facilitates the acquisition and reinstatement of cocaine-seeking behavior when administered to ovariectomized (OVX) rats. In contrast, progesterone (P) decreases acquisition of cocaine self-administration, but the effects of P on the reinstatement of drug seeking are not known. The purpose of the present study was to compare the effects of EB and P on the reinstatement of cocaine-seeking behavior in female rats. Rats received either OVX or sham surgery (SH) and were trained to lever press for intravenous cocaine infusions (0.4 mg/kg) under a fixed ratio 1, 20-s time-out schedule during daily 2-hr sessions. After 14 days of stable responding, saline replaced cocaine, and a 21-day extinction period began. After extinction, rats were separated into 5 treatment groups (OVX+EB, OVX+EB+P, OVX+vehicle [VEH], SH+P, or SH+VEH), and VEH, EB, or EB+P was administered 30 min prior to each session for 5 days. After 3 days of hormone treatment, rats received a saline or cocaine (10 mg/kg) injection, and reinstatement of lever responding was assessed. Reinstatement responding in the OVX+EB group was greater relative to the OVX+EB+P, SH+P, and OVX+VEH groups, which had low levels of cocaine-primed responding. The SH+VEH and OVX+EB groups displayed similar high levels of cocaine-elicited reinstatement. The suppression of cocaine-induced reinstatement following P treatment suggests a role for P in the prevention of relapse to cocaine self-administration in female cocaine users.     

Metabolic and energy balance in small- and appropriate-for-gestational-age, very low-birth-weight infants

This study compared nutrient utilization and postnatal weight gain composition in eight appropriate for gestational age (AGA: birth weight 1293 ± 107 g; gestational age 28.8 ± 1.4 weeks) and eight symmetrically growth-retarded (SGA: birth weight 1110 ± 230 g; gestational age 32.7 ± 1.9 weeks), very low-birth-weight (VLBW) infants. There was no significant difference in protein, mineral and energy intake between AGA and SGA infants. Nitrogen absorption (84 ± 3 and 83 ± 4%) and nitrogen retention (356 ± 48 and 352 ± 43 mg/kg/day) were similar in both groups. Fat absorption tended to be lower in AGA (78 ± 15%) than in SGA (87 ± 4%) infants. Calcium, phosphorus and magnesium absorptions were similar in AGA and SGA infants. Metabolizable energy utilization was similar in both groups; about 55% was expended and 45% stored in new tissues. Energy expenditure was 58 ± 4 kcal/kg/day in SGA infants and 61 ± 9 kcal/kg/day in AGA infants. Weight gain and its composition were similar in both groups. We conclude that nutrient and energy utilization are similar in AGA and symmetrically growth-retarded, VLBW infants.     

Whole body bone mineral content in healthy children and adolescents

Data from healthy children are needed to evaluate bone mineralisation during childhood. Whole body bone mineral content (BMC) and bone area were examined by dual energy x ray absorptiometry (Hologic 1000/W) in healthy girls (n = 201) and boys (n = 142) aged 5-19 years. Centile curves for bone area for age, BMC for age, bone area for height, and BMC for bone area were constructed using the LMS method. Bone mineral density calculated as BMC/bone area is not useful in children as it is significantly influenced by bone size. Instead, it is proposed that bone mineralisation is assessed in three steps: height for age, bone area for height, and BMC for bone area. These three steps correspond to three different causes of reduced bone mass: short bones, narrow bones, and light bones.     

GABAergic systems in the vestibular nucleus and their contribution to vestibular compensation

GABA and the GABAA and GABAB receptors play a pivotal role in the coordination of the central vestibular pathways. The commissural inhibition, which exists between the two vestibular nucleus complexes (VNCs) and which is responsible for enhancing the dynamic sensitivity of VNC neurons to head acceleration, is known to be substantially mediated by GABA acting on GABAA and GABAB receptors. After unilateral vestibular deafferentation (UVD), the large asymmetry in spontaneous resting activity between the two VNCs is reinforced and exacerbated by the GABAergic interaction between the ipsilateral and contralateral sides. Although it has been suggested that reduced GABAergic inhibition of the ipsilateral VNC may be partially responsible for the recovery of resting activity that underlies vestibular compensation of the static symptoms of UVD, at present there are few data available to test this hypothesis systematically. There is some evidence that GABA concentrations change in the ipsilateral VNC during the development of compensation; however, it is unclear whether these changes relate to GABA release or to metabolic pools of GABA. Most biochemical studies of GABA receptors have been conducted at the gene expression level. Therefore, it is unclear whether changes in the receptor protein also occur, although the most recent data suggest that changes in GABAA and GABAB receptor density in the VNC are unlikely. The few radioligand binding data relate to GABAA receptors with benzodiazepine binding sites only. A decrease in the sensitivity of ipsilateral VNC neurons from compensated animals to GABA receptor agonists has been reported; however, these studies have employed brainstem slices and therefore the functional identity of the neurons involved has been unclear. Although it seems likely that some changes in central GABAergic systems accompany the recovery of resting activity in the ipsilateral VNC during the development of vestibular compensation, at the present stage there is no compelling evidence that these changes have a causal role in the compensation process.     

A controlled trial of health education in the physician's office

Screening of 6,144 patients in a general practice clinic to assist physician case-finding uncovered 983 (16%) who were uncontrolled hypertensives. Following physician recommendation, 115 patients volunteered for a controlled trial to test the effectiveness of supplementary strategies to the pharmaceutical management of high blood pressure. A study of nonparticipants indicated that about 7% of the practice population was eligible for cardiovascular health education. One group received a health education program, a second was allocated to self-monitor their blood pressure for 6 months, a third group was allocated to both strategies, and the final group, acting as a control, continued to receive their usual care. Physician monitoring of patients continued for the duration of the study and blood pressures decreased in all patients. The study's most important outcome was the joint reduction of blood pressure and medication strength. These were assessed by a "blind" clinician before and after the interventions according to criteria set out in the "stepped-care" approach to management of high blood pressure. People allocated to a health education program conducted in the doctor's common room did twice as well on this measure as those who were not so educated. Daily self-monitoring of blood pressure for 6 months proved to be too much for the majority of those so instructed. It is concluded that the general practice setting remains an important place for health education to prevent cardiac disease and suggestions are made for incorporating this into everyday practice.     

GABA<Subscript>A</Subscript> receptor subunit expression in the guinea pig vestibular nucleus complex during the development of vestibular compensation

The aim of this experiment was to investigate whether vestibular compensation following unilateral vestibular deafferentation (UVD) is associated with changes in the expression of GABA_A receptor subunits in the guinea pig vestibular nuclear complex (VNC) at 2, 10, and 30 h post-surgery. Using Western blotting, the ₁ and ₂ subunits (but not the ₂ subunit) were detected in the VNC of labyrinthine-intact animals. However, there were no significant differences in the protein expression of the ₁ and ₂ subunits within the ipsilateral or contralateral VNC at any time post-UVD compared to sham and anesthetic controls. Furthermore, UVD did not induce the expression of the ₂ protein. These results suggest that vestibular compensation in guinea pig, as in the rat, is not associated with changes in the protein levels of the GABA_A receptor subunits ₁, ₂, and ₂ in the VNC. However, a limitation of this study is that the Western blotting technique can detect only changes that are larger than 30% and therefore small changes cannot be excluded.     

Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition

The introduction of the proteasome inhibitor bortezomib into treatment regimens for myeloma has led to substantial improvement in patient survival. However, whilst bortezomib elicits initial responses in many myeloma patients, this haematological malignancy remains incurable due to the development of acquired bortezomib resistance. With other patients presenting with disease that is intrinsically bortezomib resistant, it is clear that new therapeutic approaches are desperately required to target bortezomib-resistant myeloma. We have previously shown that targeting sphingolipid metabolism with the sphingosine kinase 2 (SK2) inhibitor K145 in combination with bortezomib induces synergistic death of bortezomib-naïve myeloma. In the current study, we have demonstrated that targeting sphingolipid metabolism with K145 synergises with bortezomib and effectively resensitises bortezomib-resistant myeloma to this proteasome inhibitor. Notably, these effects were dependent on enhanced activation of the unfolded protein response, and were observed in numerous separate myeloma models that appear to have different mechanisms of bortezomib resistance, including a new bortezomib-resistant myeloma model we describe which possesses a clinically relevant proteasome mutation. Furthermore, K145 also displayed synergy with the next-generation proteasome inhibitor carfilzomib in bortezomib-resistant and carfilzomib-resistant myeloma cells. Together, these findings indicate that targeting sphingolipid metabolism via SK2 inhibition may be effective in combination with a broad spectrum of proteasome inhibitors in the proteasome inhibitor resistant setting, and is an approach worth clinical exploration.     

Community-acquired Staphylococcus aureus bacteraemia in patients who do not abuse intravenous drugs

Despite advances in antimicrobial therapy and intensive care support, Staphylococcus aureus continues to cause significant morbidity and mortality. We studied community-acquired S. aureus bacteraemia in a population where intravenous drug abuse is extremely uncommon, prospectively reviewing all such patients (n = 113) admitted to Groote Schuur Hospital from February 1986 to January 1991. Overall mortality was 35%. Factors associated with poor outcome were: confusion on presentation, failure to mount a febrile response, acute renal failure, adult respiratory distress syndrome, shock, endocarditis, disseminated intravascular coagulation and platelet count of < 100 x 10(9)/l. Only confusion, acute renal failure and shock were independently associated with death by stepwise regression analysis. Skin infections were the most commonly identified source of bacteraemia (22%), but in 58% of patients the source was not determined. Twenty-six percent of patients were diabetic. Almost all patients (90%) developed one or more complications. In those who survived, therapy was generally prolonged, with a median of 70 days and range of 7-393 days, depending on the associated complications. Community-acquired S. aureus bacteraemia is a serious condition associated with a high complication rate and mortality.