International survey of perceived barriers to admission and discharge from spinal cord injury rehabilitation units.

STUDY DESIGN: Survey. OBJECTIVES: To describe and compare perceived barriers with patient flow in spinal rehabilitation units (SRUs). SETTING: International. Ten SRUs (Australia, Canada, India, Ireland, Italy, Netherlands, Pakistan, Switzerland, UK and USA) that admit both traumatic and non-traumatic spinal cord injury patients. METHODS: Survey completed between December 2010 and February 2013 on perception of barriers for admission into and discharge from SRUs. Opinion was sought from the participants regarding the utility of collecting data on the timeliness of access to SRUs and occurrence of discharge barriers for benchmarking and quality improvement purposes. RESULTS: The perceived barriers in accessing SRUs ranged from no access problem to a severe access problem (no access problems n=3; minor access problems n=3; moderate access problems n=2; severe access problem n=1 and extreme n=1). Most units (n=9/10) agreed that collecting data on timeliness of access to SRUs for acute hospital patients may help improve patient outcomes and health system processes by providing information for benchmarking and quality improvement purposes. All units reported perceived barriers to discharge from SRUs. Compared with admission barriers, a greater perception of barriers to discharge was reported (minor problem n=3; moderate problem n=3; severe problem n=3; and extreme n=1). All units agreed that collecting data on barriers to discharge from SRU may help improve patient outcomes and system processes. CONCLUSIONS: Perceived barriers to patient flow in SRUs are reported in many countries. Projects to identify and minimise the occurrence and impact of admission and discharge barriers could increase access to rehabilitation and improve the rehabilitation outcomes for patients.

International comparison of the organisation of rehabilitation services and systems of care for patients with spinal cord injury.

STUDY DESIGN: Survey. OBJECTIVES: Describe and compare the organisation and delivery of rehabilitation services and systems of care for patients with spinal cord injury (SCI). SETTING: International. Nine spinal rehabilitation units that manage traumatic SCI and non-traumatic SCI (NTSCI) patients. METHODS: Survey based on clinical expertise and literature review. Completed between November 2010 and April 2011. RESULTS: All units reported public/government funding. Additional funding sources included compensation schemes, private insurance and self funding. Six units had formal attachment to an acute SCI unit. Five units (Italy, Ireland, India, Pakistan and Switzerland) provided a national service; two units (the Netherlands and USA) provided regional and two units (Australia and Canada) provided state/provincial services. The median number of SCI rehabilitation beds was 23 (interquartile range=16-30). All units admitted both traumatic SCI and NTSCI patients. The median proportion of patients admitted who had traumatic SCI was 45% (IQR 20-48%) and 40% (IQR 30-42%) had NTSCI. The rehabilitation team in all centres determined patient readiness for discharge. There was great variability between units in the availability of SCI speciality services, ancillary services and staff/patient ratios. CONCLUSION: There was a wide range of differences in the organisation, systems of care and services available for patients with SCI in rehabilitation units in different countries. Understanding these differences is important when comparing patient outcomes from different settings. A standardised collection of these system variables should be considered as part of future studies and could be included in the ISCoS data set project.

Acute flaccid paraplegia: a rare complication of meningococcal meningitis.

STUDY DESIGN: A case report of spinal cord dysfunction following meningococcal meningitis. OBJECTIVES: To describe a rare complication of meningococcal meningitis. SETTING: Spinal Unit, Armed Forces Institute of Rehabilitation Medicine, Rawalpindi, Pakistan. METHODS: A young healthy male developed meningococcal meningitis followed by acute onset low thoracic flaccid paraplegia with complete motor and sensory loss and sphincter disturbance. He responded well to antibiotics but was not investigated for causes of paraplegia. While at home in a rural area, he developed pressure ulcers, anemia and depression. Magnetic resonance imaging of the whole spine and computed tomography scan of the brain performed after 4 and 10 weeks were normal. RESULTS: The patient had a comprehensive rehabilitation at our institute. Recovery was complicated by ossification in the right thigh, which responded well to radiotherapy. At 1-year follow-up, the motor deficit and neurogenic bladder and bowel persisted and the patient remained wheelchair dependent for mobility. CONCLUSION: Several mechanisms have been proposed to explain spinal cord damage after meningitis. These include spinal cord infarction; autoimmune-mediated inflammatory myelopathy and direct infection of the cord. Most probable cause of spinal cord dysfunction in this case was thoracic myelopathy.

Epidemiology of spinal cord injuries in the 2005 Pakistan earthquake.

STUDY DESIGN: Prospective observational study. OBJECTIVES: To identify the epidemiological features specific to spinal injuries as a result of an earthquake. SETTINGS: Rawalpindi, Pakistan in the months after the 8 October 2005 earthquake. METHODS: In the month after the earthquake, the one established rehabilitation center was augmented with two makeshift spinal cord centers. Information on mechanism of injury, mode of evacuation, associated injuries was gathered, and a detailed clinical and radiological assessment was performed. Neurological status and functional outcome was determined after 10 weeks. RESULTS: Of an estimated 650-750 spinal cord injuries, 187 were admitted to these centers, including 80 men and 107 women with a mean age of 28.3+/-12.4 years. Injuries occurred while standing in 57.8% of patients. Most (83.4%) who reached the spinal cord center were airlifted. A urinary catheter had been placed before admission in 91.5%. Most of the patients were paraplegic 89.3, with 50.8% incomplete injuries. Fracture or fracture dislocation was present in 70, and 75% underwent spinal fixation. Although pressure ulcers (28.9%) and urinary tract infections (39%) were common, deep venous thromboses (4.8%) and depression (5.8%) were seldom detected. At 10 weeks, 75% were continent or performing intermittent catheterization. There were no deaths and two births. CONCLUSION: After a disaster, evacuation of persons with a spinal cord injury to a specialized center results in low mortality. Response planning for disasters should include early aggressive medical rehabilitation.

A tool for assessing 'readiness' in emergency obstetric care: the room-by-room 'walk-through'.

This article presents a tool that can be used to assess the readiness of a health facility to provide emergency obstetric care. The 'walk-through' tool is a checklist that follows the physical path that a woman and her caregivers might follow. The items on the checklist are critical to an enabling environment in which skilled providers can save lives. The article explains how the tool can be used and by whom, and it describes several experiences in the field.

Experience from Bangladesh: implementing emergency obstetric care as part of the reproductive health agenda.

This paper describes the activities of the Ministry of Health and Family Welfare of the Government of Bangladesh and UNFPA to introduce emergency obstetric care (EmOC) services into the reproductive health care agenda. Working through the existing system of Maternal and Child Welfare Centers (MCWC), the quality and availability of comprehensive Reproductive Health and Emergency Obstetric Care services was improved. Investments in training, infrastructure, management information systems, quality assurance mechanisms and linkages between health care facilities in Bangladesh, have produced positive results in terms of increased utilization of these services. The Ministry of Health first implemented services in one division of the country and later scaled up to include all of the MCWCs nationally. While there are still obstacles to preventing obstetric deaths in Bangladesh, this experience shows that improvements in the quality and expansion of the range of services in existing health systems is an important step toward increasing the use of reproductive health care services by the women who need them most.

Differential IGF-independent effects of insulin-like growth factor binding proteins (1-6) on apoptosis of breast epithelial cells.

We have demonstrated previously that insulin-like growth factor binding protein (IGFBP)-3 alone has little growth inhibitory effect on Hs578T human breast cancer cells, but that it can dramatically accentuate the apoptotic response to the physiological trigger, ceramide, in an IGF-independent manner. We have now studied the potential of other IGFBPs (1-6) to interact with apoptotic signalling pathways. Hs578T cells were preincubated with a binding protein (100 ng/ml) for 24 h, followed by co-incubation of the binding protein with an apoptotic dose of ceramide or RGD-containing peptide for a further 24 h. Apoptosis was assessed using flow cytometry, MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; thiazolyl blue) assay and morphological assessment. Binding protein profiles were determined using ligand and immunoblotting techniques. Each of the IGFBPs (1-6) alone had no significant (P > 0. 05) growth inhibitory effects relative to control cells. In contrast to IGFBP-3, which significantly (P < 0.05) accentuated C2-induced apoptosis, IGFBP-1, -2, and -6 had no effect, whereas IGFBP-4 and -5 each caused marked (P < 0.01) inhibition of ceramide-induced programmed cell death. Apoptosis induced by RGD was also significantly (P < 0.05) reduced by IGFBP-5, whereas IGFBP-3 had no effect. These data provide evidence to suggest that individual IGFBPs have specific IGF-independent effects and act differentially on apoptotic signalling pathways.

The role of cell surface attachment and proteolysis in the insulin-like growth factor (IGF)-independent effects of IGF-binding protein-3 on apoptosis in breast epithelial cells.

We have recently reported that insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) can significantly increase ceramide-induced apoptosis in an Hs578T breast carcinoma cell line in an IGF-independent manner. It was observed in that study that IGFBP-3 added to the cultures was proteolytically modified, generating a specific pattern of fragmentation. We have also previously reported that almost all of the IGFBP-3 outside the circulation in extravascular fluids is in a fragmented form, apparently due to the activity of a cation-dependent serine protease. The aim of this study was to investigate the role of proteolysis in the IGFBP-3 enhancement of C2-induced apoptosis. In this study we confirmed that preincubation of Hs578T cells with IGFBP-3 enhances the apoptotic effect of the ceramide analog C2. The presence of IGF-I completely inhibited the enhancement effect, apparently by inhibiting cell surface association and proteolytic modification. The presence of a serine protease inhibitor [4-(2-aminoethyl)benesulfonyl fluoride] completely inhibited the enhancement effect of IGFBP-3, and Western immunoblotting of conditioned medium and cell surface-associated IGFBP-3 revealed that proteolytic fragmentation of the IGFBP-3 was reduced. In addition, fragments from the incubation of IGFBP-3 with plasmin were able to enhance the susceptibility of Hs578T cells to C2. The effect of these fragments could, however, also be reduced by 4-(2-aminoethyl)benesulfonyl fluoride despite the fact that IGFBP-3 was already fragmented. This suggests additional roles for serine proteases in the IGFBP-3 effect on C2-induced apoptosis in addition to the cleavage of the binding protein.

Activation of integrin and ceramide signalling pathways can inhibit the mitogenic effect of insulin-like growth factor I (IGF-I) in human breast cancer cell lines.

Cell counting, cell cycle analysis and Western immunoblotting were used to examine the effects of non-apoptotic doses of a ceramide analogue, C2, and a synthetic arginine-glycine-aspartic acid (RGD)-containing peptide, RGD, in MCF-7 and T47D cells to determine whether activation of these signalling pathways could alter the mitogenic potential of insulin-like growth factor I (IGF-I). IGF-I alone increased total cell number in both cell lines, associated with a rise in the percentage of cells in the S-phase of the cell cycle and a co-incident increase in cyclin A production. Treatments alone had no effects on cell number or cyclin A production relative to controls. C2 inhibited IGF-I-induced mitogenesis in both lines, whereas RGD was only effective in the T47D line. Despite inhibition of cell proliferation, IGF-I stimulation of cells in S-phase and of cyclin A levels were unaffected; however, an IGF-I-induced increase in cyclin B1 levels was inhibited by 30%. Low-dose induction of integrin and ceramide signalling pathways causes cells to be blocked in S-phase, thereby inhibiting the normal cycle of events associated with the IGF-I-induced mitotic signal. Activating these pathways may not only restrict tumour growth by induction of apoptosis but they may also directly inhibit IGF-I-induced cell proliferation.

Release of superoxide dismutase activity from human umbilical veins by heparin.

OBJECTIVE: This study evaluated superoxide dismutase activity released from human umbilical veins incubated with different doses of heparin and examined at different time points. STUDY DESIGN: Umbilical veins of fresh cords from full term babies were incubated with 175 or 1 U/ml of heparin at one end while the other end was incubated without heparin as control. Specimens were obtained at 10 minutes and 24 hours (high-dose) or at 10 minutes and 60 minutes (low-dose). Superoxide dismutase activity was measured by the cytochrome c method. Results were analyzed using Student's paired t test. RESULTS: A time-dependent release of superoxide dismutase activity into the buffer was observed in both heparin specimens as well as in control specimens. The difference in release in the presence of heparin was of statistical significance, compared with the controls. CONCLUSION: Because heparin is routinely used as an anticoagulant to maintain the patency of umbilical catheters, we conclude that this usage may alter a newborn's response to oxygen free radical damage by changes in superoxide dismutase activity.

Insulin-like growth factor-binding protein (IGFBP-3) predisposes breast cancer cells to programmed cell death in a non-IGF-dependent manner.

Insulin-like growth factor (IGF) -independent growth inhibition of human breast cancer cells, Hs578T, by IGF-binding protein-3 (IGFBP-3) has previously been demonstrated. Cell growth is a balance between proliferation and programmed cell death (apoptosis). We have investigated whether IGFBP-3 can affect apoptosis of Hs578T cells. As no induction of apoptosis was found, we also investigated its effect on the response to ceramide, an intracellular second messenger that mediates the signal for apoptosis. Using the cell permeable ceramide analogue, C2, induction of apoptosis was established by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay, trypan blue uptake, morphological criteria, and flow cytometry. Incubation of cells with non-glycosylated IGFBP-3 (ngIGFBP-3; 0.5-100 ng/ml) resulted in no growth inhibition or increase in apoptosis; whereas, C2 (1-30 microM) resulted in a dose-dependent induction of apoptosis. Addition of IGFs to the cells, alone or with C2, elicited no response in terms of proliferation or survival, respectively. When the cells were preincubated with ngIGFBP-3 before addition of C2 (2-5 microM), apoptosis was accentuated in a dose-dependent manner (at 100 ng/ml IGFBP-3, apoptosis increased from 11 to 88%). In conclusion, we found that IGFBP-3 had no direct inhibitory effect on Hs578T cells but could accentuate apoptosis induced by the physiological trigger ceramide in an IGF-independent manner.

The role of endogenous serotonin in adjuvant-induced arthritis in the rat.

We have investigated the effects of serotonin depletion on the progress and severity of adjuvant-induced arthritis in the Piebald-Viral-Glaxo (PVG) strain of rat. Total body depletion of serotonin was achieved using p-chlorophenylalanine given i.p. Two paradigms were investigated. First we depleted serotonin at the time of injection of the adjuvant to determine whether serotonin was involved in the initial induction phase. Secondly, we depleted serotonin at the time of onset of the inflammation. Serotonin levels in the hypothalamic paraventricular nucleus (PVN) were reduced by > 95%. Depletion at the time of induction had no effect on the severity of the disease (determined by the increase (determined by the increase in hind paw volume) 14 days after injection of the adjuvant. In contrast, depletion at the time of onset of the disease resulted in a significant reduction in severity at day 14, suggesting a pro-inflammatory role for serotonin in this model. The decrease in corticotrophin-releasing factor (CRF) mRNA in the PVN associated with the development of adjuvant arthritis in PVG rat was reversed in the serotonin-depleted animals. Central serotonin could be one of the factors responsible for the reduced expression of CRF mRNA in response to adjuvant-induced arthritis in this rat strain. These data suggest that serotonin antagonists may be efficacious in reducing the severity of acute inflammatory episodes.

A protective role for testosterone in adjuvant-induced arthritis.

We have investigated the role of the gonadal steroids testosterone (T) and progesterone in modulating: (1) the onset and severity of adjuvant-induced arthritis (AA), (2) the response of the hypothalamo-pituitary-adrenal (HPA) axis, and (3) the levels of plasma prolactin and anterior pituitary prolactin messenger ribonucleic acid (mRNA) in the rat. Male rats were castrated (CSX) and received either no T, low T or high T delivered using silastic implants. In a second study experimental groups comprised CSX/AA, CSX/AA + progesterone or CSX/AA + progesterone + T. The time of onset was sooner and the severity of AA was greater in CSX rats. Inflammation was prevented by T replacement. Endogenous plasma T levels were decreased in AA rats. In control animals with AA there was an increase in pro-opiomelanocortin (POMC) mRNA in the anterior pituitary and of plasma corticosterone, and a decrease in corticotrophin-releasing factor (CRF) mRNA. These changes in the HPA axis of AA and CSX/AA rats were reversed by T replacement. These data suggest that T has an important protective effect on the progress and severity of AA. This was reflected by a reversal of the neuroendocrine changes of the HPA axis. Progesterone treatment alone had no effect on the severity of the disease. Prolactin mRNA in the anterior pituitary was decreased in the CSX and in the CSX/AA group but was not altered by AA. Plasma prolactin was raised in AA but T replacement did not reduce these elevated levels despite the absence of disease. Thus, prolactin provides a poor indicator of inflammation, suggesting that it may not be a potent pro-inflammatory compound in AA.

Leg ulcers in patients with sickle cell disease.

During the entry examination, leg ulcers were present in 2.5% of 2,075 patients 10 years of age and older with sickle cell disease who entered into the Cooperative Study of Sickle Cell Disease (CSSCD) between 1979 and 1986. Prevalence rates were highest among patients with sickle cell anemia and sickle cell anemia with thalassemia genotypes. Among sickle cell anemia patients free of ulcers at entry, the overall incidence was 5.73 per 100 person years in those having associated alpha-thalassemia and 9.97 for those without. Among sickle cell anemia patients with two alpha genes, the estimated incidence of leg ulcers is 2.38 per 100 person years and 6.12 per 100 person years among sickle cell anemia patients with three alpha genes (P less than .05). In both groups, the incidence was highest among those patients over 20 years of age and considerably higher among males than females (P less than .001). Leg ulcers were nonexistent in patients with sickle beta plus thalassemia and sickle hemoglobin C disease. Low steady-state hemoglobin is associated with a higher incidence of ulcer formation (P less than .0001) in sickle cell anemia patients. The protective effect of hemoglobin F is apparent at all levels of total hemoglobin among sickle cell anemia patients and those with associated alpha-thalassemia.

How community pharmacy staff manage a patient with possible oral cancer.

Community pharmacy staff were surveyed for the advice they would offer to a patient with a history highly suggestive of oral carcinoma. Less than 10% of 57 pharmacies indicated that a dental or medical opinion should be sought. This study confirms that the knowledge of pharmacy staff about oral disease is as limited as it is about systemic disease and suggests that a dental or medical consultation is necessary for persisting complaints.

Recruitment in the Cooperative Study of Sickle Cell Disease (CSSCD).

The Cooperative Study of Sickle Cell Disease (CSSCD) is a multiinstitutional investigation of the natural history of clinical course of sickle cell disease from birth through adulthood. The study is not a trial; rather, it involves data collection at 23 institutions in a uniform, standardized fashion on 3800 patients. Recruitment aspects that were addressed include issues related to recruitment of different age groups, ranging from newborns to pregnant women to patients over 50 years of age; the need to include mildly affected patients to ensure that the study would not reflect only a severe hospital-based population; recruitment from rural populations; and the need to screen and enter a newborn population at birth. The recruitment goal of entering 3200 patients, including 2100 patients with SS hemoglobinopathy, over a 24-month period was accomplished after 27 months.