Could the GMC institute an appeal procedure?
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Humans↗
Biomedical subjects
G Graham
Publications and source records attributed to G Graham.
HIV-1 RNA load in needles/syringes from shooting galleries in Miami: a preliminary laboratory report.
We quantified HIV-1 RNA load in rinses from needles/syringes (N/S) obtained at shooting galleries in Miami and also analyzed the rinses for antibodies for viral proteins. In rinses from 36 N/S that contained visible blood, 14 (39%) had detectable amounts of HIV-1 RNA. Numbers of copies of HIV-1 RNA ranged from the detection limit (400 copies/ml) to 268,000 copies/ml. We also detected antibodies to HIV-1 polypeptides in 34/36 (94%) of rinses from visibly contaminated N/S using Western blots specific for the HIV-1 proteins. No antibodies were detected in laboratory rinses from six visibly clean needles. The presence of HIV-1 RNA in N/S is an important indication of the risk created by N/S sharing as well as by shared paraphernalia and wash waters by injecting drug users.
Blotting, Western↗
Probing for relevance: what metacognition tells us about the power of consciousness.
Metacognitive attitudes can affect behavior but do they do so, as Koriat claims, because they enhance voluntary control? This Commentary makes a case for saying that metacognitive consciousness may enhance not control but subjective predictability and may be best studied by examining not just healthy, well-integrated cognizers, but victims of multilevel mental disorders.
Behavior↗
Genital tract electrical burns during hysteroscopic endometrial ablation: report of 13 cases in the United States and Canada.
We investigated 13 alleged thermal injuries to the genital tract of women undergoing hysteroscopic endometrial ablation. Possible mechanisms proposed to explain these injuries are hot-weighted speculum, povidone-iodine scrub solution, inadequate rinsing of Cidex sterilizing solution, and electrical burns. The history, nature, and distribution, as well as experimental evidence strongly support the hypothesis that these injuries are electrical due to capacitive coupled currents induced onto the sheath of the resectoscope, and/or stray currents generated by arcing or direct coupling from defective electrode insulation to the telescope, electrifying the entire resectoscope.
Adult↗
Adenocarcinoma of the lung: electron microscopy of fine-needle aspiration biopsy specimens--a review of 73 cases.
During a 10-yr period, 128 consecutive cases of pulmonary adenocarcinoma of varying differentiation were diagnosed with percutaneous fine-needle aspiration biopsy. Sediments from the needle and syringe washings with 3% glutaraldehyde were obtained and processed for electron microscopic evaluation in 73 cases. Our results showed three types of adenocarcinoma: 62 cases of nonciliated bronchiolar cell origin, 6 cases of bronchioloalveolar cell origin, and 3 cases of mucous cell origin. In addition, there was an example of combined adenosquamous carcinoma and an instance of amphicrine carcinoma. Our study provided a more precise definition of the cytologic diagnosis and insight into the heterogeneity of lung adenocarcinoma. However, prognostic differences between cell types of lung adenocarcinoma were not observed.
Adenocarcinoma↗
Etoposide as a virocidal anticytomegalovirus therapy: intravitreal toxicology and pharmacology in rabbits.
BACKGROUND: Although Cytomegalovirus (CMV) retinitis is now a common intraocular infection, current therapy is only virostatic so ongoing treatment is required. Etoposide was found to be virocidal for CMV in laboratory experiments and it might prove to be beneficial clinically. We investigated the toxicity and intraocular concentration of etoposide (VP16) and its new analogue etoposide-phosphate (VP16P) following intravitreal injections in rabbit eyes. METHODS: First a sequential dose-response was assessed with flash electroretinogram for both eyes of light- and dark-adapted rabbits (n = 7; one rabbit for each dose) over a range of light intensities before and after intravitreal injection of VP16 or VP16P to one eye; the other eye was injected with normal saline as a control. A multidose study was then performed on four rabbits. A non-toxic dose of VP16P (50 or 75 g) was injected into the vitreous of one eye on four occasions 1 week apart. A photopic electroretinogram was performed before the first injection and 6 weeks after the last injection. All the eyes from the electroretinogram studies were fixed in formalin, placed in paraffin, then stained with haematoxylin and eosin and examined under a light microscope. To determine the time-course of the intraocular concentrations of VP16P a sequential pharmacokinetic study was performed using a further 12 rabbits. Each rabbit was injected with 50 g VP16P to one eye and 75 g VP16P to the other eye. Three of these rabbits were killed at 1, 3, 6 and 9 h after injection. Samples of vitreous were assayed for both VP16 and VP16P using HPLC. An in vitro dose response assay was performed using third-passage bovine retinal pigment epithelial (RPE) cells cultured in Dulbecco's modified Eagles medium with fetal calf serum. The effect of a log-dose increment of VP16P on the RPE cell proliferation was assessed using tritiated thymidine incorporation. RESULTS: The electroretinogram studies suggested that VP16 was toxic even with the 10 g dose. For VP16P a toxic effect was noted following injection of a single dose greater than 100 g. Multiple injections of 50 or 75 g VP16P did not produce a toxic response. Histological examination demonstrated significant abnormality only with the 500 g dose of VP16 or VP16P. VP16P was rapidly metabolized to VP16 in the eye, producing concentrations of 2.0 g/mL or more for up to 9 h following a 75-microg dose. This suggests that the electroretinogram findings following VP16 injections were confounded by a toxic effect of the ethanol solvent (which is absent from the VP16P preparation). VP16P was quite potent, the ID50 was about 0.1 g/mL for bovine RPE cells in the in vitro assay. DISCUSSION: These results indicate that multiple 75-gVP16P intravitreal injections were not toxic to the rabbit eye and provide a therapeutic intraocular concentration for up to 9 h after the injection.
Animals↗
Neuregulin is a mitogen and survival factor for olfactory bulb ensheathing cells and an isoform is produced by astrocytes.
The rat olfactory bulb is an exceptional CNS tissue. Unlike other areas of the brain, growing axons are able to enter the olfactory bulb and extend within this CNS environment throughout adult life. It appears that the glial cells of the olfactory system, known as olfactory bulb ensheathing cells (OBECs), may have an important role in this remarkable process of CNS neural regeneration. OBECs are unusual glial cells, possessing properties of both astrocytes and Schwann cells. In this study we show that astrocytes (in the form of astrocyte-conditioned medium; ACM) produce two critical regulatory functions for OBECs: mitogenic activity and a survival factor. Interestingly, the ACM-derived activity for OBECs appears to reside in a signalling protein(s) belonging to the neuregulin (NRG) family of growth factors, and specifically appears to coincide with one or more products of the nrg-1 gene. Our observations provide evidence for the following: recombinant human neu differentiation factors (NDFbeta1, -2 and -3) are mitogenic to OBECs; the activity in ACM can be neutralized by NDF antibodies; these same antibodies detect a 50-kDa, non-heparin binding protein in concentrated ACM; astrocytes express detectable nrg-1 transcripts; and OBECs express functional NRG receptors erbB2 and erbB4.
Animals↗
Risk factors for sleep-disordered breathing in children. Associations with obesity, race, and respiratory problems.
This study examined risk factors for sleep-disordered breathing (SDB) in children and adolescents; specifically, quantifying risk associated with obesity, race, and upper and lower respiratory problems. Subjects were participants in a genetic-epidemiologic study of SDB and included 399 children and adolescents 2 to 18 yr of age, recruited as members of families with a member (a proband) with known sleep apnea (31 index families) or as members of neighborhood control families (30 families). SDB was assessed with home overnight multichannel monitoring and SDB was defined based on an apneahypopnea index >/= 10 (moderately affected) or < 5 (unaffected). SDB of moderate level was significantly associated with obesity (odds ratio, 4.59; 95% confidence interval [CI], 1.58 to 13.33) and African-American race (odds ratio, 3.49; 95% CI, 1.56 to 8.32) but not with sex or age. After adjusting for obesity, proband sampling, race and familial clustering, sinus problems and persistent wheeze each independently (of the other) predicted SDB. These data suggest the importance of upper and lower respiratory problems and obesity as risk factors for SDB in children and adolescents. Increased risk in African Americans appears to be independent of the effects of obesity or respiratory problems.
Adolescent↗
EST analysis of gene expression in early cleavage-stage sea urchin embryos.
A set of 956 expressed sequence tags derived from 7-hour (mid-cleavage) sea urchin embryos was analyzed to assess biosynthetic functions and to illuminate the structure of the message population at this stage. About a quarter of the expressed sequence tags represented repetitive sequence transcripts typical of early embryos, or ribosomal and mitochondrial RNAs, while a majority of the remainder contained significant open reading frames. A total of 232 sequences, including 153 different proteins, produced significant matches when compared against GenBank. The majority of these identified sequences represented 'housekeeping' proteins, i.e., cytoskeletal proteins, metabolic enzymes, transporters and proteins involved in cell division. The most interesting finds were components of signaling systems and transcription factors not previously reported in early sea urchin embryos, including components of Notch and TGF signal transduction pathways. As expected from earlier kinetic analyses of the embryo mRNA populations, no very prevalent protein-coding species were encountered; the most highly represented such sequences were cDNAs encoding cyclins A and B. The frequency of occurrence of all sequences within the database was used to construct a sequence prevalence distribution. The result, confirming earlier mRNA population analyses, indicated that the poly(A) RNA of the early embryo consists mainly of a very complex set of low-copy-number transcripts.
Animals↗
How to resolve stool retention in a child. Underwear soiling is not a behavior problem.
Many parents do not realize their child has stool retention when they bring him or her for an office visit. Some complaints that may be a tip-off and should prompt questioning about stool frequency and underwear soiling are vague abdominal pain, urinary incontinence, and stools so large they plug the toilet. A rectal examination is usually adequate to confirm the diagnosis. Management begins with educating parents that leaking of liquid stool around impaction and onto underwear is completely involuntary, so the child should never be scolded or embarrassed. Stool retention may begin because of unpleasant or unavailable toilet facilities, constipation, or painful elimination and often becomes self-perpetuating. Impaction must be removed immediately; magnesium citrate solution is usually effective. To allow the rectum to return to its normal size, which can take an extended time, stool must be kept soft and movable with administration of mineral oil and appropriate dietary choices (eg, fruit, juice, fiber). Recurrence is common, so ongoing measures and follow-up are important.
Cathartics↗
Suspension of consultant raises serious issues.
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Consultants↗
Laparoscopic cholecystectomy during pregnancy: a case series and review of the literature.
This study was conducted to evaluate the role of antepartum laparoscopic cholecystectomy (LC). Patients who underwent LC were identified from a hospital database with the use of CPT/ICD codes. Of 2093 cases performed at a major center (October 1991 to November 1997), only six were performed during pregnancy. On reviewing the English literature, gestational age at surgery and delivery and outcome of delivery were provided in only 69 of 105 patients (33 papers with 1-10 cases) and we tabulated different variables from the cases in this review. In this series, two patients who had LC in the first trimester underwent elective termination of pregnancy. Of the seven published cases of first trimester LC followed to delivery, one had preterm delivery. First trimester open cholecystectomy (OC) has a 12 percent spontaneous abortion rate. The four patients who had second trimester LC had normal deliveries at term. Of the 43 published cases of second trimester LC followed to delivery, 39 ended in uncomplicated, full-term deliveries. Three of four second trimester cases at one institution had spontaneous abortions. None of our patients underwent LC in the third trimester. Of the 12 published cases of third trimester LC followed to delivery, one had preterm delivery. Third trimester OC is reported to have a 40 percent rate of preterm delivery. There were no intraoperative cholangiograms (IOC), prophylactic or postoperative use of tocolytics, or intraoperative fetal monitoring in our series. We added six cases of LC during pregnancy to the previously reported 105 cases. The successful outcome in all trimesters suggests that LC is a safe procedure throughout pregnancy; however, surgery in the second trimester is preferable. Compared with OC, there is a decreased risk of spontaneous abortion in the first trimester and preterm labor in the third trimester.
Abortion, Spontaneous↗
Acute stroke teams: results of a national survey. National Acute Stroke Team Group.
BACKGROUND AND PURPOSE: The sensitivity of the brain to brief periods of profound ischemia or prolonged periods of modest ischemia mandates an aggressive approach to acute stroke care. Past studies have shown that many stroke patients do not receive acute care in an urgent and timely fashion. The formation of acute stroke teams (AST) is one approach that can be used to accelerate the delivery of acute stroke care. METHODS: We conducted a survey of major stroke program directors and neurovascular experts throughout the United States. The survey focused on issues related to the presence of AST, their staffing, operational features, and utilization at the surveyed programs and hospitals. RESULTS: Surveys were returned from 45 of 60 centers. Ninety-one percent of the respondents indicated that they currently had an AST, with 66% formed between 1995 and 1997. Staffing of ASTs consisted of attending physicians (95%), nurses or study coordinators (73%), fellows (49%), and residents (46%). In almost all cases (98%), the AST was led by a neurologist or neurosurgeon, and 98% of the ASTs operated on a 24-hours-per-day, 7-days-per-week basis. The most common call frequency was 2 to 3 times per week (41%), followed by >5 calls per week (29%). In 59% of the cases, the teams cost </=$5000 per year to operate. The vast majority (78%) of ASTs responded within 10 minutes of receiving a call. CONCLUSIONS: The formation of ASTs is quite common at the surveyed programs. Although staffing patterns vary, most teams are led by neurologists or neurosurgeons. The utilization of ASTs varies by facility, but they appear to be useful, with only a modest incremental financial cost. The use of ASTs may assist in providing more rapid medical care to stroke patients and increase the use of some acute therapies. Extension of the AST concept to nonacademic hospitals appears feasible.
Academic Medical Centers↗
Phenotypic variability in Friedreich ataxia: role of the associated GAA triplet repeat expansion.
We studied genotype-phenotype correlations in a group of 100 patients with typical Friedreich ataxia (FRDA), and in three groups of patients with atypical clinical presentations, including 44 Acadian FRDA, 8 late-onset FRDA (LOFA), and 6 FRDA with retained reflexes (FARR). All patients, except 3 with typical FRDA, carried two copies of the FRDA-associated GAA triplet repeat expansion. Overall, the phenotypic spectrum of FRDA appeared to be wider than defined by the currently used diagnostic criteria. Our study indicated the existence of several sources of variability in FRDA. Patients with larger GAA expansions tended to have earlier onset and were more likely to show additional manifestations of the disease. Mitotic instability of the expanded GAA repeats may partially account for the limited degree of correlation between expansion sizes as determined in lymphocytes and clinical parameters. Some clinical variants associated with specific FRDA haplotypes, such as Acadian FRDA and FARR, turned out to be unrelated to expansion sizes. No polymorphism in the frataxin coding sequence could be associated with these clinical variants.
Adolescent↗
Acute intermittent porphyria: the in vitro expression of mutant hydroxymethylbilane synthase.
Acute intermittent porphyria (AIP) is an inborn error of haem biosynthesis caused by a variety of mutations in the gene coding for hydroxymethylbilane synthase (HMB-S). The entire coding sequence of this gene, from each of three South African AIP patients, was therefore screened for mutations using chemical cleavage mismatch (CCM) analysis and any changes detected characterized by DNA sequencing. Three single base changes were identified; a G77 to A in exon 3, a C346 to T in exon 8 and a G518 to A in exon 10. These missense mutations, previously reported to be present in other populations, are known to be responsible for the structurally deleterious amino acid replacements R26H, R116W and R173Q, respectively. The in vitro expression of the enzymes containing these mutations and the subsequent measurement of their specific activities revealed a reduction to approximately 4% of normal activity.
Escherichia coli↗
Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins.
Aggregation and retention of LDL in the arterial wall are key events in atherogenesis, but the mechanisms in vivo are not known. Previous work from our laboratories has shown that exposure of LDL to bacterial sphingomyelinase (SMase) in vitro leads to the formation of LDL aggregates that can be retained by extracellular matrix and that are able to stimulate macrophage foam cell formation. We now provide evidence that retained LDL is hydrolyzed by an arterial-wall SMase activity. First, we demonstrated that SMase-induced aggregation is caused by an increase in particle ceramide content, even in the presence of excess sphingomyelin (SM). This finding is compatible with previous data showing that lesional LDL is enriched in SM, though its ceramide content has not previously been reported. To address this critical compositional issue, the ceramide content of lesional LDL was assayed and, remarkably, found to be 10-50-fold enriched compared with plasma LDL ceramide. Furthermore, the ceramide was found exclusively in lesional LDL that was aggregated; unaggregated lesional LDL, which accounted for 20-25% of the lesional material, remained ceramide poor. When [3H]SM-LDL was incubated with strips of rabbit aorta ex vivo, a portion of the LDL was retained, and the [3H]SM of this portion, but not that of unretained LDL, was hydrolyzed to [3H]ceramide by a nonlysosomal arterial hydrolase. In summary, LDL retained in atherosclerotic lesions is acted upon by an arterial-wall SMase, which may participate in LDL aggregation and possibly other SMase-mediated processes during atherogenesis.
Animals↗
Glutathione deficiency as a complication of methylmalonic acidemia: response to high doses of ascorbate.
A 7-year-old boy with deficient activity of methylmalonyl coenzyme A mutase (mut-methylmalonic acidemia) was seen in severe metabolic crisis. After hemodialysis and clearance of toxic metabolites, severe lactic acidosis persisted with multiorgan failure. Glutathione deficiency was noted and high-dose ascorbate therapy (120 mg/kg) commenced. Glutathione deficiency may contribute to the lactic acidosis observed during decompensation in patients with methylmalonic acidemia.
Acidosis, Lactic↗
High dose intravitreal ganciclovir injection provides a prolonged therapeutic intraocular concentration.
BACKGROUND: Although intravitreal high dose ganciclovir has previously been found to provide excellent control of cytomegalovirus (CMV) retinitis, little was known about the vitreous concentrations of ganciclovir after a 2 mg intravitreal injection. METHODS: Eleven vitreous samples were taken from seven patients with CMV retinitis at 24 and 72 hours after a 2 mg intravitreal injection of ganciclovir and the concentration of ganciclovir was measured by high performance liquid chromatography. RESULTS: The mean concentration of ganciclovir at 24 hours was 143.8 mg/l (95% confidence interval 97.8-190) and at 72 hours was 23.4 mg/l (95% CI 0-49.7). The half life ranged from 11.9 to 26.3 (mean 18.8) hours in the four patients who had two samples taken. The mean half life calculated from the mean concentrations at 24 and 72 hours was 18.3 hours, so the calculated mean concentration at 7 days was 0.6 mg/l. CONCLUSIONS: This suggests that it takes about 7 days to eliminate the intravitreal ganciclovir, and that it is not likely to accumulate with weekly injections. The intravitreal concentrations achieved with high dose therapy remained above the ID50 for CMV (0.25-1.22 mg/l) for up to 7 days.
Antiviral Agents↗