Diagnostic trajectory, interplay and convergence/divergence across all 12 DSM-IV psychotic diagnoses: 6-year follow-up of the Cavan-Monaghan First Episode Psychosis Study (CAMFEPS).

BACKGROUND: The boundaries of psychotic illness and the extent to which operational diagnostic categories are distinct in the long term remain poorly understood. Clarification of these issues requires prospective evaluation of diagnostic trajectory, interplay and convergence/divergence across psychotic illness, without a priori diagnostic or other restrictions. METHOD: The Cavan-Monaghan First Episode Psychosis Study (CAMFEPS), conducted using methods to attain the closest approximation to epidemiological completeness, incepts all 12 DSM-IV psychotic diagnoses. In this study we applied methodologies to achieve diagnostic reassessments on follow-up, at a mean of 6.4 years after first presentation, for 196 (97%) of the first 202 cases, with quantification of prospective and retrospective consistency. RESULTS: Over 6 years, the 12 initial psychotic diagnoses were characterized by numerous transitions but only limited convergence towards a smaller number of more stable diagnostic nodes. In particular, for initial brief psychotic disorder (BrP), in 85% of cases this was the harbinger of long-term evolution to serious psychotic illness of diagnostic diversity; for initial major depressive disorder with psychotic features (MDDP), in 18% of cases this was associated with mortality of diverse causality; and for initial psychotic disorder not otherwise specified (PNOS), 31% of cases continued to defy DSM-IV criteria. CONCLUSIONS: CAMFEPS methodology revealed, on an individual case basis, a diversity of stabilities in, and transitions between, all 12 DSM-IV psychotic diagnoses over 6 years; thus, psychotic illness showed longitudinal disrespect to current nosology and may be better accommodated by a dimensional model. In particular, a first episode of BrP or MDDP may benefit from more vigorous, sustained interventions.

Carepath for overcoming psychosis early (COPE): first 5 years of clinical operation and prospective research in the Cavan-Monaghan early intervention service.

OBJECTIVES: As Ireland confronts the many challenges of broadening the introduction of early intervention services (EIS) for first episode psychosis (FEP) as national policy, this article describes Carepath for Overcoming Psychosis Early (COPE), the EIS of Cavan-Monaghan Mental Health Service, and presents prospective research findings during its first 5 years of operation. METHODS: COPE was launched as a rural EIS with an embedded research protocol in early 2012, following an education programme for general practitioners (GPs). Here, operational activities are documented and research findings presented through to late 2016. RESULTS: During this period, 115 instances of FEP were incepted into COPE, 70.4% via their GP and 29.6% via the Emergency Department. The annual rate of inception was 24.8/100,000 of population aged > 15 years and was 2.1-fold more common among men than women. Mean duration of untreated psychosis was 5.7 months and median time from first psychotic presentation to initiation of antipsychotic treatment was zero days. Assessments of psychopathology, neuropsychology, neurology, premorbid functioning, quality of life, insight, and functionality compared across 10 DSM-IV psychotic diagnoses made at six months following presentation indicated minimal differences between them, other than more prominent negative symptoms in schizophrenia and more prominent mania in bipolar disorder. CONCLUSIONS: COPE illustrates the actuality of introducing and the challenges of operating a rural EIS for FEP. Prospective follow-up studies of the 5-year COPE cohort should inform on the effectiveness of this EIS model in relation to long-term outcome in psychotic illness across what appear to be arbitrary diagnostic boundaries at FEP.

Capillary and venous haemoglobin levels in blood donors: a 42-month study of 36,258 paired samples.

BACKGROUND: EU law requires a haemoglobin of > or = 12.5 g/dl for women or > or = 13.5 g/dl for men at the time of donation. As capillary and venous haemoglobin values may differ in the same subject, we examined whether a capillary haemoglobin level of 12.0 g/dl for women or 13.0 g/dl for men, is equivalent to a venous haemoglobin level of > or = 12.5 g/dl and > or = 13.5 g/dl, respectively, to avoid unnecessary loss of blood donations. METHODS: Over a continuous 42-month period, 36 258 paired capillary and venous samples were taken from 25 762 females and 10 496 males, when the capillary haemoglobin was < 12.5 g/dl and < 13.5 g/dl respectively. RESULTS: Venous haemoglobin levels were higher than capillary levels, with a mean difference of 1.07 g/dl (SD 0.68 g/dl), range -2.2 to +3.25 g/dl for men (P < 0.001), and a mean difference of 0.67 g/dl (SD 0.65 g/dl), range -2.5 to +5.4 g/dl for women (P < 0.001). The difference for the three consecutive winters was 0.78 g/dl (SD 0.081 g/dl) for females and 1.26 g/dl (SD 0.162 g/dl) for males and for the three consecutive summers was 0.56 g/dl (SD 0.089 g/dl) for females and 0.88 g/dl (SD 0.134 g/dl) for males: P < 0.001. CONCLUSIONS: Capillary haemoglobin levels of 12.0-12.5 g/dl in healthy females or 13.0-13.5 g/dl in healthy males are substantively equivalent to venous haemoglobin levels of > or = 12.5 and > or = 13.5 g/dl for women and men respectively. This finding has permitted an additional 32 990 blood units to be collected over the period of the study, a gain of 9.4%.

Acute colonic obstruction due to benign prostatic hypertrophy.

A seventy two year old man presented to the Emergency Department with clinical features of colonic obstruction. Subsequent radiological investigations confirmed this impression and revealed the aetiology to be compression of the sigmoid colon against the sacrum by a massively distended urinary bladder. Chronic urinary retention due to benign prostatic hypertrophy is an extremely unusual cause of large bowel obstruction. Little in this patient's clinical findings suggested this aetiology. We reviewed the literature in this area and highlight the benefits of CT scanning over contrast studies.

Screening platelet concentrates for bacterial contamination: low numbers of bacteria and slow growth in contaminated units mandate an alternative approach to product safety.

BACKGROUND AND OBJECTIVES: We introduced 100% screening of platelets for bacterial contamination in 2005 to reduce the risk of clinical sepsis from platelet transfusion. We test all outdating units again at expiry to assess the sensitivity of the initial test. MATERIALS AND METHODS: We test all platelet concentrates prior to release for clinical use using a large volume automated culture technique on the day after manufacture. All units that expire unused are retested. Platelets still in stock on day 4 of storage may have a repeat culture performed, and are returned to stock with two extra days of shelf life. RESULTS: Of 43,230 platelet units screened, 35 (0.08%) were positive; of 8282 expired unused, 18 (0.22%) were positive; and of 3310 day-4 retests, four (0.12%) were positive. Overall sensitivity of the initial screening test was 29.2% (95% confidence interval 19.4 to 39.1%). Thirteen of the 35 positive screening tests would have been expected to grow in both aerobic and anaerobic bottles; eight grew in aerobic culture only and five grew in anaerobic culture only, indicating that the likely number of bacteria in the contaminated platelet units at the time of sampling was less than 60 colony-forming unit per platelet unit. CONCLUSIONS: Screening platelet concentrates for bacterial contamination using the most sensitive method available has a sensitivity of less than 40% because of the low numbers of bacteria in the initial contamination. Effective resolution of this problem will require a pathogen-inactivation technique.

A prospective evaluation of adherence to medication in first episode schizophrenia.

The aim of this study was to identify the features of first episode schizophrenia that predict adherence antipsychotic medication at six-month follow-up. We used validated instruments to assess clinical and socio-demographic variables in all patients with first episode schizophrenia from a defined geographical area admitted to a Dublin psychiatric hospital over a four-year period (N=100). At six-month follow-up (N=60) we assessed adherence to medication using the Compliance Interview. One third of patients with schizophrenia were non-adherent with medication within six months of their first episode of illness. High levels of positive symptoms at baseline, lack of insight at baseline, alcohol misuse at baseline and previous drug misuse predict non-adherence. These results indicate that an identifiable subgroup of patients with first episode schizophrenia is at high risk of early non-adherence to medication. While high positive symptom scores pre-date and predict non-adherence in most patients, reduced insight is the best predictor of non-adherence in patients who do not misuse alcohol or other drugs.

Decreasing sensitivity to cytotoxic agents parallels increasing tumorigenicity in human fibroblasts.

Human embryo fibroblasts of common genetic origin but exhibiting a range of phenotypes from normal to aggressively tumorigenic have been used to study resistance to the cytotoxic drugs methotrexate and N-(phosphonacetyl)-L-aspartate. Measurement of the intrinsic sensitivities of these cells to the two drugs in standard survival assays, in normal fetal bovine serum, showed increasing resistance to parallel increasing tumor-igenicity. Tumor cells were totally resistant to 10 mM N-(phosphonacetyl)-L-aspartate whereas the 50% lethal dose for methotrexate for the tumor cells was 500 nM compared with 50 nM for the normal diploid parent cell line. The difference in resistance between the immortal and tumorigenic cell lines was eliminated for both methotrexate and N-(phosphonacetyl)-L-aspartate, when the experiments were repeated in the presence of dialyzed fetal bovine serum, but could be restored by the addition of either hypoxanthine (100 microM) or uridine (10 microM). This suggested an important role for the salvage pathways of purine and pyrimidine biosynthesis in the increased resistance of the more tumorigenic cell lines. The implications of these data in relation to cancer chemotherapy will be discussed.

Effect of tumor promoter 12-O-tetradecanoylphorbol-13-acetate on recovery of methotrexate-, N-(phosphonacetyl)-L-aspartate-, and cadmium-resistant colony-forming mouse and hamster cells.

The effect of the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and its nontumor promoting derivative 4-O-methyl-12-O-tetradecanoylphorbol-13-acetate on the frequency of mouse and hamster cells resistant to methotrexate (MTX), N-(phosphonacetyl)-L-aspartate, and cadmium has been examined. TPA alone at concentrations up to 1.0 microgram/ml had no significant effect on the plating efficiency of either mouse or hamster cells. Exposure of 3T3 and 3T6 mouse and V79 and Chinese hamster ovary cells at low density to the 3 compounds in the presence of TPA (0.1 microgram/ml) did not result in any increase in the recovery of resistant colonies. When plated at high density, exposure to drug selection in the presence of TPA resulted in a 3- to 10-fold increase overall in the incidence of MTX-, N-(phosphonacetyl)-L-aspartate-, and cadmium-resistant mouse cells. However, an increase greater than 3-fold was not observed in hamster cells exposed to drug plus TPA under the same conditions. 4-O-Methyl-12-O-tetradecanoylphorbol-13-acetate had no significant effect on the frequency of MTX-resistant cells. Seventy V79 cell clones surviving MTX (200 to 400 nM) alone and 79 surviving MTX plus TPA were isolated and retested for resistance to MTX. None were stable. In contrast, 6 out of 42 mouse colonies isolated from MTX alone and 55 out of 99 isolated from MTX plus TPA showed stable resistance on retesting in MTX. The implications of these results in relation to possible mechanisms of tumor promotion are discussed.

A cadaveric study of the distribution pattern of the cutaneous sensory fibres of the distal palm of the hand.

We investigated the cutaneous innervation of the distal palm, an area frequently dissected by the hand surgeon. Ten (five paired) fresh-frozen cadaveric hands were dissected under 3.0× loupe magnification. Volar branches were found on both sides in the majority of digits. They originated alongside, or at the proximal margin of, the A1 pulley in 84% of digits. The mean distance from the palmar digital crease to the origin of volar branches was 21 mm.

Mental illness self-management: a randomised controlled trial of the Wellness Recovery Action Planning intervention for inpatients and outpatients with psychiatric illness.

OBJECTIVE: Wellness Recovery Action Planning (WRAP) is a cross-diagnostic, patient-centred, self-management intervention for psychiatric illness. WRAP utilises an individualised Wellness Toolbox, a six part structured monitoring and response system, and a crisis and post-crisis plan to promote recovery. The objective of this study was to evaluate the effect of WRAP on personal recovery, quality of life, and self-reported psychiatric symptoms. METHOD: A prospective randomised controlled trial, based on the CONSORT principles was conducted using a sample of 36 inpatients and outpatients with a diagnosis of a mental disorder. Participants were randomly allocated to Experimental Group or Waiting List Control Group conditions in a 1:1 ratio. Measures of personal recovery, personal recovery life areas, quality of life, anxiety, and depression were administered at three time points: (i) pre-intervention, (ii) post-Experimental Group intervention delivery, and (iii) 6-month follow-up. Data was analysed by available case analysis using univariate and bivariate methodologies. RESULTS: WRAP had a significant effect on two personal recovery life areas measured by the Mental Health Recovery Star: (i) addictive behaviour and (ii) identity and self-esteem. WRAP did not have a significant effect on personal recovery (measured by the Mental Health Recovery Measure), quality of life, or psychiatric symptoms. CONCLUSIONS: Findings indicate that WRAP improves personal recovery in the areas of (i) addictive behaviour and (ii) identity and self-esteem. Further research is required to confirm WRAP efficacy in other outcome domains. Efforts to integrate WRAP into recovery-orientated mental health services should be encouraged and evaluated.

Evidence for geographical variations in the prevalence of schizophrenia in rural Ireland.

Geographical variations in the rate of occurrence of schizophrenia have been the subject of much speculation and controversy, but it has proved extremely difficult to establish the existence of the phenomenon within a given study area. Using current inpatient and outpatient records and information from key informants active in the community, this study sought to identify all cases of schizophrenia in 36 District Electoral Divisions, constituting a clinical catchment area of 25,178 persons in a rural Irish county. Though the overall prevalence rate (3.3 per 1000) was unremarkable, this obscured a substantial and significant variation in prevalence rates (from 0.0 to 14.3 per 1000) between District Electoral Divisions. Prevalence rates in five District Electoral Divisions made particular contributions to the overall deviation from a statistical model for random occurrences in space. The results indicate spatial inhomogeneity in the prevalence of schizophrenia in rural Ireland and imply geographical variation in environmental or genetic factor(s) of etiologic relevance.

Cognitive dysfunction, negative symptoms, and tardive dyskinesia in schizophrenia. Their association in relation to topography of involuntary movements and criterion of their abnormality.

Little is known of factors that, on an individual basis, confer vulnerability to the emergence of involuntary movements (tardive dyskinesia) during long-term neuroleptic treatment. In this study of 88 chronic schizophrenic inpatients, 22 variables (four demographic, 14 medication history, and four features of illness) were compared for any association(s) with the presence, by differing topographies and criteria of abnormality, and severity of involuntary movements. Irrespective of the criterion used, the presence of marked cognitive dysfunction-muteness bore a consistent and highly significant primary association with both the presence and the overall severity of orofacial dyskinesia; no such association was found in relation to the presence of limb-truncal dyskinesia. Flattening of affect was the only other variable consistently associated with the presence of orofacial movements. The reliability and prominence of the association between the presence of orofacial, but not of limb-truncal, movements and cognitive dysfunction-negative symptoms suggest that these varying topographies may not constitute a unitary syndrome. This strong association, not with indexes of neuroleptic exposure but rather with features of the illness for which that treatment was prescribed, suggests some neurologic process, more subtle than may previously have been appreciated, as a vulnerability factor of some importance. In schizophrenia it appears to be intimately related to the disease process.

Long-term adaptive life functioning in relation to initiation of treatment with antipsychotics over the lifetime trajectory of schizophrenia.

BACKGROUND: There is evidence that the stage of illness at which antipsychotic treatment is initiated in schizophrenia may have consequences for its subsequent course. How this might relate to impaired adaptive life functioning in the long-term is poorly understood. METHODS: Thirty-eight inpatients, many of whom had been admitted in the preneuroleptic era, were assessed using the Social-Adaptive Functioning Evaluation (SAFE); constituent clinical and medication phases of the lifetime trajectory of their illnesses were then analyzed to identify predictors of SAFE score using multiple regression modeling. RESULTS: The primary, independent predictor of SAFE score was duration of initially unmedicated psychosis, which accounted for 22% of variance (p<.001) therein. Conversely, duration of subsequently treated illness, although decades longer, failed to predict SAFE score. CONCLUSIONS: These findings are consistent with some form of "progressive" process, particularly over the first several years following the emergence of psychosis, which is associated with accrual of deficits in adaptive life functioning.

The relationship of minor physical anomalies and other putative indices of developmental disturbance in schizophrenia to abnormalities of cerebral structure on magnetic resonance imaging.

Minor physical anomalies, together with obstetric complications, family history, and handedness status, were assessed to explore putative neurodevelopmental disturbance(s) in patients with schizophrenia whose cerebral structure had been examined previously by magnetic resonance imaging. Minor physical anomalies were related to negative symptoms in males and to premorbid intellectual function in females, but not to ventricular volume; however, three patients with evident neurodevelopmental anomalies of the ventricular system showed prominent minor physical anomalies. In exploratory analyses, obstetric complications were associated with left ventricular asymmetry, and a positive family history with inverse profiles of asymmetry in males vs. females; non-right-handedness was associated with increased ventricular volume in males but with poorer premorbid intellectual function in females. This nexus of relationships and their gender specificities suggest early dysmorphogenesis in schizophrenia that is related to sexual dimorphism.

Familial, obstetric, and other clinical correlates of minor physical anomalies in schizophrenia.

OBJECTIVE: This study investigated possible antecedents of minor physical anomalies in schizophrenia, particularly in terms of obstetric and genetic factors, and demographic, clinical and cognitive correlates of such anomalies in schizophrenia. METHOD: Forty-one outpatients satisfying the DSM-III criteria for schizophrenia were examined for minor physical anomalies by using the Waldrop scale. These subjects were drawn from a group of 45 such patients whose cognitive function had been previously evaluated with Trail Making Tests A and B and whose biological mothers had been interviewed for any history of obstetric complications or family history of schizophrenia. RESULTS: Linear multiple regression analysis showed that higher scores for minor physical anomalies were associated with impaired cognitive flexibility on Trail Making Test B, family history of schizophrenia in a first-degree relative, maternal history of obstetric complications, smaller number of siblings, later position in the birth order, and male sex. A family history of schizophrenia was particularly associated with abnormalities of the mouth. The association between minor physical anomalies in the patients and obstetric complications in their mothers appeared to be confined to instances in which the mother had a history of bleeding in early pregnancy. CONCLUSIONS: Minor physical anomalies indicate early dysmorphogenesis in schizophrenia, particularly in males, which appears to be associated more reliably with genetic rather than obstetric factors and with cognitive impairment.

The phorbol ester, TPA inhibits glucagon-stimulated adenylate cyclase activity.

The ability of glucagon (10 nM) to increase hepatocyte intracellular cyclic AMP concentrations was reduced markedly by the tumour-promoting phorbol ester TPA (12-O-tetradecanoyl phorbol-13-acetate). The half-maximal inhibitory effect occurred at 0.14 ng/ml TPA. This action occurred in the presence of the cyclic AMP phosphodiesterase inhibitor isobutylmethylxanthine (1 mM) indicating that TPA inhibited glucagon-stimulated adenylate cyclase activity. TPA did not affect either the binding of glucagon to its receptor or ATP concentrations within the cell. TPA did inhibit the increase in intracellular cyclic AMP initiated by the action of cholera toxin (1 microgram/ml) under conditions where phosphodiesterase activity was blocked. TPA did not inhibit glucagon-stimulated adenylate cyclase activity in a broken plasma membrane preparation unless Ca2+, phosphatidylserine and ATP were also present. It is suggested that TPA exerts its inhibitory effect on adenylate cyclase through the action of protein kinase C. This action is presumed to be exerted at the point of regulation of adenylate cyclase by guanine nucleotides.

Combined suicide and granulocyte-macrophage colony-stimulating factor gene therapy induces complete tumor regression and generates antitumor immunity.

The use of prodrug-activated ("suicide") gene therapy has been shown to be effective in inducing tumor regression when only a small proportion of tumor cells contains the suicide gene. These experiments were designed to test whether additional therapeutic benefit may be obtained by stimulating the immune response. Murine MC26 colon carcinoma cells, either untransduced or transduced with genes for herpes simplex virus-1 thymidine kinase (HSV1-TK) or human GM-CSF, were injected subcutaneously into syngeneic BALB/c mice in various combinations. Inoculation of equal numbers of untransduced and HSV1-TK-containing cells followed by ganciclovir (GCV) treatment resulted in almost complete tumor regression, but by 7 weeks, tumors had recurred in all mice. A similar initial regression was obtained using equal numbers of cells containing HSV1-TK and GM-CSF genes, but >80% of these mice remained tumor-free after 3 months. Groups of tumor-free mice that had received GM-CSF-containing cells were left for different periods of time and rechallenged with unmodified MC26 cells on the opposite flank. Of the mice rechallenged 14, 28, and 108 days later, 100%, 88%, and 57%, respectively, showed complete resistance to unmodified tumor cells. In mice that showed tumor regrowth, tumor volume was much less than in control mice. Adoptive transfer of spleen cells from resistant mice to naïve syngeneic mice resulted in partial resistance to challenge with unmodified tumor cells. Specific cytotoxicity against MC26 cells was only demonstrable in mice receiving GM-CSF- and HSV1-TK-containing tumor cells. These experiments show that the presence of cells secreting GM-CSF in HSV1-TK-containing, regressing tumor is able to induce complete or partial resistance to tumor rechallenge. This indicates the potential usefulness of GM-CSF in enhancing other antitumor therapies.

Prodrug-activated gene therapy: involvement of an immunological component in the "bystander effect".

The integration and expression of the herpes simplex virus type 1 thymidine kinase (HSV1-TK) gene in localized tumors results in tumor regression after the administration of the specific nucleoside analogue ganciclovir (GCV). Although only 10% to 20% of the tumor cells take up the HSV1-TK gene, the neighboring cells also die, a phenomenon termed "bystander effect.". In the present study, coinjection of the MC26 mouse colon carcinoma cell line and the HSV1-TK expressing retroviral packaging cell line followed after 7 days by the intraperitoneal administration of GCV resulted in almost total tumor regression in the immunocompetent BALB/c mice but not in immunocompromised athymic BALB/c mice. This suggested a strong cell-mediated immune component to the bystander effect.

Reduced E-cadherin expression correlates with increased invasiveness in colorectal carcinoma cell lines.

A reduction in cell adhesiveness and cell invasion are essential steps in tumour progression to metastasis. In the present study two out of seven colorectal carcinoma cell lines exhibited reduced expression of the cell-cell adhesion molecule E-cadherin as assessed by immunofluorescence. The same two cell lines were invasive in the collagen gel and membrane invasion culture system invasion assays. Addition of anti-E-cadherin antibody to a non-invasive carcinoma cell line caused the cells to assume a dissociated morphology on plastic and to become invasive in collagen gels. This demonstrates a causal role for E-cadherin in the maintenance of intercellular adhesion and the suppression of tumour cell invasion and possibly metastasis in colorectal tumour cells.

Topographical Assessment of Ethological and Dopamine Receptor Agonist-Induced Behavioral Phenotype in Mutants with Congenic DARPP-32 'Knockout'.

Congenic (10 backcrosses into C57BL/6J) mutants with targeted gene deletion of DARPP-32, a neuronal phosphoprotein regarded as an essential mediator of the biological effects of dopamine (DA), were assessed phenotypically using an ethologically based approach that resolves all topographies of behavior in the mouse repertoire. Over initial exploration, female, but not male, DARPP-32 mutants evidenced increased locomotion and decreased grooming, while a decrease in rearing seated was evident in mutants of both genders; continuing assessment over several hours did not reveal additional phenotypic effects. Following challenge with the nonselective DA receptor agonist apomorphine, low doses were associated with reduced levels of sniffing, grooming, total rearing, and rearing seated in DARPP-32 mutants relative to wildtypes; this would suggest some role for DARPP-32 in mediating the biological effects of presynaptic D(2)-like autoreceptor or inhibitory postsynaptic D(2)-like receptor activation. Following challenge with higher doses, while stereotyped sniffing and locomotion with chewing was largely unaltered, the additional murine response of Straub tail was essentially abolished in DARPP-32 mutants, indicating some specific involvement of DARPP-32 in mediating this topography of behavior; additionally, there were overall reductions in levels of sniffing, total rearing, rearing seated, and grooming in DARPP-32 mutants that were unrelated to the dose of apomorphine administered, indicating broader topographical effects following the stress of the injection procedure relative to more naturalistic conditions. The developmental absence of DARPP-32 following targeted gene deletion appears to be associated with compensatory processes that maintain certain topographies of spontaneous and agonist-induced DAergic function, while other topographies remain impaired.