Ictal face perception disturbance, tattoos, and reclaiming the self.

We present a case of a young man with frightening ictal disturbance of face perception, or prosopometamorphopsia, arising from the left temporo-occipital region, leading to significant psychosocial impairment. A vivid forearm tattoo of the ictal experience conveyed its nature to the treating team and facilitated a psychotherapeutic process leading to significant psychosocial recovery. This case highlights the marked psychosocial and developmental impacts of epilepsy and the benefit of incorporating these into assessment and treatment.

Interpersonal sensitivity in the at-risk mental state for psychosis.

BACKGROUND: Interpersonal sensitivity is a personality trait described as excessive awareness of both the behaviour and feelings of others. Although interpersonal sensitivity has been found to be one of the vulnerability factors to depression, there has been little interest in its relationship with the prodromal phase of psychosis. The aims of this study were to examine the level of interpersonal sensitivity in a sample of individuals with an at-risk mental state (ARMS) for psychosis and its relationship with other psychopathological features. METHOD: Sixty-two individuals with an ARMS for psychosis and 39 control participants completed a series of self-report questionnaires, including the Interpersonal Sensitivity Measure (IPSM), the Prodromal Questionnaire (PQ), the Ways of Coping Questionnaire (WCQ) and the Depression and Anxiety Stress Scale (DASS). RESULTS: Individuals with an ARMS reported higher interpersonal sensitivity compared to controls. Associations between interpersonal sensitivity, positive psychotic symptoms (i.e. paranoid ideation), avoidant coping and symptoms of depression, anxiety and stress were also found. CONCLUSIONS: This study suggests that being 'hypersensitive' to interpersonal interactions is a psychological feature of the putatively prodromal phase of psychosis. The relationship between interpersonal sensitivity, attenuated positive psychotic symptoms, avoidant coping and negative emotional states may contribute to long-term deficits in social functioning. We illustrate the importance, when assessing a young client with a possible ARMS, of examining more subtle and subjective symptoms in addition to attenuated positive symptoms.

The HSV-2 mutant DeltaPK induces melanoma oncolysis through nonredundant death programs and associated with autophagy and pyroptosis proteins.

Malignant melanoma is a highly aggressive and drug-resistant cancer. Virotherapy is a novel therapeutic strategy based on cancer cell lysis through selective virus replication. However, its clinical efficacy is modest, apparently related to poor virus replication within the tumors. We report that the growth compromised herpes simplex virus type 2 (HSV-2) mutant, DeltaPK, has strong oncolytic activity for melanoma largely caused by a mechanism other than replication-induced cell lysis. The ratio of dead cells (determined by trypan blue or ethidium homodimer staining) to cells that stain with antibody to the major capsid protein VP5 (indicative of productive infection) was 1.8-4.1 for different melanoma cultures at 24-72 h post-infection. Cell death was due to activation of calpain as well as caspases-7 and -3 and it was abolished by the combination of calpain (PD150606) and pancaspase (benzyloxycarbonyl-Val-Ala-Asp-fluormethyl ketone, z-VAD-fmk) inhibitors. Upregulation of the autopahgy protein Beclin-1 and the pro-apoptotic protein H11/HspB8 accompanied DeltaPK-induced melanoma oncolysis. Intratumoral DeltaPK injection (10(6)-10(7) plaque-forming unit (pfu)) significantly reduced melanoma tumor burden associated with calpain and caspases-7 and -3 activation, Beclin-1 and H11/HspB8 upregulation and activation of caspase-1-related inflammation. Complete remission was seen for 87.5% of the LM melanoma xenografts at 5 months after treatment termination. The data indicate that DeltaPK is a promising virotherapy for melanoma that functions through virus-induced programmed cell death pathways.

A review of geriatric injuries at a major trauma centre in South Africa.

BACKGROUND: Trauma in South Africa (SA) has been referred to as a malignant epidemic, but the impact of trauma on the elderly has tended to be overlooked. OBJECTIVES: To address this deficit by focusing on trauma victims aged ≥65 years. METHODS: All patients aged ≥65 years who were admitted to Grey's Hospital, Pietermaritzburg, SA, following trauma between December 2012 and January 2019 were reviewed. RESULTS: Over the 6-year study period, a total of 281 patients aged ≥65 years were admitted to Grey's Hospital following trauma. There were 150 males (53.4%) and 97 females (34.5%). The sex of 34 patients was unknown. The average age was 72 years (range 65 - 97). There were 226 cases of blunt trauma, 42 cases of penetrating trauma (including two incidents of impalement following blunt trauma) and 15 cases of other types of trauma. The most common causes of blunt trauma were accidental falls (n=76), motor vehicle accidents (n=46), pedestrian vehicle accidents (n=32) and falls from a height (n=23). Gunshot wounds (n=22) and knife wounds (n=14) were the most common forms of penetrating trauma. Other trauma mainly comprised dog bites (n=6) and snakebites (n=6). There were 72 incidents of assault (25.6% of total cases). The majority of assaults were committed by a single perpetrator, and the perpetrator was frequently known to the victim. There were no significant differences in the proportions of penetrating, blunt and other trauma injuries between males and females. A total of 44 patients (15.7%) required surgical intervention, and 41 patients (14.6%) experienced complications during their hospitalisation. Respiratory, renal and cardiac complications were most frequent, and 5 patients had a cardiac arrest. Seven experienced acute kidney injury. Seventeen patients (6.0%) required intensive care unit admission and 5 (1.8%) required ventilation. Patients stayed in hospital for an average of 2.96 days (range 0 - 39). Of the patients, 241 (85.8%) survived, 32 (11.4%) died and 8 (2.9%) had an unknown outcome. CONCLUSIONS: Geriatric trauma in SA is relatively rare, but will increase as the population ages. There is a high incidence of assault as a mechanism, highlighting the fact that elderly people are a vulnerable group. Managing these patients is challenging and is associated with significant morbidity and mortality.

Overload of the heat-shock protein H11/HspB8 triggers melanoma cell apoptosis through activation of transforming growth factor-beta-activated kinase 1.

Molecular therapeutics is a recognized promising approach for melanoma, but relevant target genes remain elusive. We report that overload of the recently cloned H11/HspB8 induces apoptosis in 55% of examined melanoma cultures. Apoptosis was determined by activation of caspases-9 and -3 and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), and was not seen in normal melanocytes. It was associated with H11/HspB8 complexation with transforming growth factor-beta-activated kinase (TAK) 1 and activation of TAK1 and p38 mitogen activated protein 3 kinases. TAK1 was not bound, nor activated by the H11/HspB8 mutant W51C, which has dominant antiapoptotic activity. beta-Catenin was phosphorylated by activated TAK1, inhibiting its nuclear accumulation and mictophthalmia-associated transcription factor and cyclin dependent kinase 2 expression. The dominant-negative TAK1 mutant K63W inhibited beta-catenin phosphorylation and caspase activation. The data indicate that H11/HspB8 overload causes melanoma growth arrest and apoptosis through TAK1 activation and suggest that H11/HspB8 is a promising molecular therapy target.

ICP10PK inhibits calpain-dependent release of apoptosis-inducing factor and programmed cell death in response to the toxin MPP+.

Apoptosis is a widely accepted component of the pathogenesis of Parkinson's disease (PD), a debilitating neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. However, additional death programs were implicated, and current understanding of the cycle of intracellular events that leads to the demise of these neuron Jis limited. Gene therapy strategies were proposed to inhibit apoptosis, but they have met with relatively limited success. Here we report that the antiapoptotic herpes simplex virus type 2 gene ICP10PK protects neuronally differentiated PC12 cells from death caused by 1-methyl-4-phenylpyridinium (in vitro PD model) through inhibition of calpain I activation and the resulting inhibition of Bax translocation to the mitochondria, apoptosis-inducing factor release and caspase-3 activation. Neuroprotection is through ICP10PK-mediated activation of the PI3-K/Akt survival pathway and upregulation/stabilization of the antiapoptotic protein Bcl-2 and the cytoprotective chaperone heat-shock protein 70.

Connexin expression and turnover : implications for cardiac excitability.

Electrical activation of the heart requires current transfer from one cell to another via gap junctions, arrays of densely packed intercellular channels. The extent to which cardiac myocytes are coupled is determined by multiple mechanisms, including tissue-specific patterns of expression of diverse gap junction channel proteins (connexins), and regulatory pathways that control connexin synthesis, intracellular trafficking, assembly into channels, and degradation. Many connexins, including those expressed in the heart, have been found to turn over rapidly. Recent studies in the intact adult heart suggest that connexin43, the principal cardiac connexin, is surprisingly short-lived (half-life approximately 1.3 hours). Both the proteasome and the lysosome participate in connexin43 degradation. Other ion channel proteins, such as those forming selected voltage-gated K(+) channels, may also exhibit rapid turnover kinetics. Regulation of connexin degradation may be an important mechanism for adjusting intercellular coupling in the heart under normal and pathophysiological conditions.

Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia.

Electrical uncoupling at gap junctions during acute myocardial ischemia contributes to conduction abnormalities and reentrant arrhythmias. Increased levels of intracellular Ca(2+) and H(+) and accumulation of amphipathic lipid metabolites during ischemia promote uncoupling, but other mechanisms may play a role. We tested the hypothesis that uncoupling induced by acute ischemia is associated with changes in phosphorylation of the major cardiac gap junction protein, connexin43 (Cx43). Adult rat hearts perfused on a Langendorff apparatus were subjected to ischemia or ischemia/reperfusion. Changes in coupling were monitored by measuring whole-tissue resistance. Changes in the amount and distribution of phosphorylated and nonphosphorylated isoforms of Cx43 were measured by immunoblotting and confocal immunofluorescence microscopy using isoform-specific antibodies. In control hearts, virtually all Cx43 identified immunohistochemically at apparent intercellular junctions was phosphorylated. During ischemia, however, Cx43 underwent progressive dephosphorylation with a time course similar to that of electrical uncoupling. The total amount of Cx43 did not change, but progressive reduction in total Cx43 immunofluorescent signal and concomitant accumulation of nonphosphorylated Cx43 signal occurred at sites of intercellular junctions. Functional recovery during reperfusion was associated with increased levels of phosphorylated Cx43. These observations suggest that uncoupling induced by ischemia is associated with dephosphorylation of Cx43, accumulation of nonphosphorylated Cx43 within gap junctions, and translocation of Cx43 from gap junctions into intracellular pools.

Long term follow-up of c-myc, p53 and proliferation measurements in malignant melanoma.

AIMS: We report a prospective study examining the prognostic significance of the c-myc oncoprotein, p53 tumour suppressor gene and proliferation rate measurements in malignant melanoma. METHODS: Flow cytometry (FCM) was used to measure the expression of c-myc, p53 and proliferation parameters in patients who had received an injection of the thymidine analogue bromodeoxyuridine prior to surgery. RESULTS: Sixty-seven patients had successful FCM measurements of the three parameters. c-myc was detected in 97% of patients with a median cell positivity of 62%. The median p53 positivity was 13%. The median potential doubling time (T(pot)) of the tumours wasf 9.4 days. In univariate analysis, each of the parameters showed an association with survival in metatstatic disease with rapid proliferation (p=0.006) or overexpression of c-myc (p=0.038) related to poor survival whereas increased positivity for p53 predicted better survival (p=0.013). CONCLUSIONS: These data indicate that laser cytometric technology can be used to obtain quantitative data on oncoproteins expression and cell proliferation rates in clinical samples of malignant melanoma.

Reconstruction of disruptions of the deep transverse metacarpal ligament of the ring finger using the A1 pulleys.

There is little information in the literature regarding the clinical features, investigation, diagnosis and treatment of closed rupture of the deep transverse metacarpal ligament. We demonstrate a case with previously undescribed features and describe the surgical management.

Proteolysis of connexin43-containing gap junctions in normal and heat-stressed cardiac myocytes.

OBJECTIVE: The present studies were performed to examine the degradation of connexin43-containing gap junctions by the lysosome or the proteasome in normal and heat-stressed cultures of neonatal rat ventricular myocytes. METHODS: Primary cultures were prepared from neonatal rat ventricular myocytes. Connexin43 was detected by immunoblotting, immunofluorescence, or immunoprecipitation. Gap junction profiles were detected by transmission electron microscopy. RESULTS: Immunoblots of whole cell lysates demonstrated increased levels of connexin43 in cultures treated with lysosomal inhibitors (chloroquine, leupeptin, E-64, or ammonium chloride) or proteasomal inhibitors (lactacystin or ALLN). Pulse-chase experiments showed that the half-life of connexin43 was 1.4 h in control cultures, but was prolonged to 2.0 or 2.8 h in cultures treated with chloroquine or lactacystin, respectively. Immunofluorescence and electron microscopy showed a significant increase in the number of gap junction profiles in myocytes treated with either chloroquine or lactacystin. Heat treatment of cultures (43.5 degrees C for 30 min) produced a rapid loss of connexin43 as detected by immunoblotting or immunofluorescence. Heat-induced connexin43 degradation was prevented by simultaneous treatment with lactacystin, ALLN, or chloroquine. Connexin43 levels and distribution returned to normal by 3 h following a heat shock and were resistant to a subsequent repeat heat stress. The heat shock also led to production of HSP70 as detected by immunoblotting. CONCLUSIONS: These data suggest that Cx43 gap junctions in myocytes are degraded by the proteasome and the lysosome, that this proteolysis can be augmented by heat stress, and that inducible factors such as HSP70 may protect against Cx43 degradation.

Bullying victimisation and paranoid ideation in people at ultra high risk for psychosis.

BACKGROUND: Bullying victimisation has been suggested to contribute to paranoid ideation in general population samples and recent evidence found that individuals with an ultra high risk (UHR) for psychosis are twice as likely to have been bullied than controls. AIMS: This study sought to examine whether a history of bullying would be associated with higher levels of paranoid ideation in individuals with an UHR and in healthy controls (HCs). METHOD: The study included 64 UHR and 43 HC participants. Following the baseline assessment, participants entered a Virtual Reality (VR) London Underground train. Paranoid ideation was measured immediately after the end of the VR experience. RESULTS: Compared to HCs, UHR participants described higher levels of childhood bullying (OR 5.19, 95% CI=2.21-12.19, p<.001) and experienced more paranoid ideation during VR (χ(2)(1)=21.06, p<.001). Childhood bullying was associated with paranoid ideation during VR in both groups (χ(2)(1)=5.931, p=,021) but prolonged exposure to bullying was not associated with increased paranoid ideation. CONCLUSION: A history of bullying in childhood is particularly common in young adults at high risk for psychosis. However bullying is associated with paranoid ideation in later life, independent of clinical status, consistent with dimensional models of psychotic phenomena.

Connexin45 interacts with zonula occludens-1 in osteoblastic cells.

Connexin43 (Cx43) and Cx45 are co-expressed in a number of different tissues. Studies demonstrated that Cx45 transfected ROS (ROS/Cx45) cells, were less permeable to low molecular weight dyes than untransfected ROS cells, that have gap junctions made of Cx43. This suggests that there may be a functionally important interaction between Cx43 and Cx45 in these cells. One way in which these proteins may interact is by associating with the same set of proteins. In order to isolate connexin interacting proteins, we isolated Cx45 from Cx45 transfected ROS cells (ROS/Cx45 cells) under mild detergent conditions. These studies showed that Cx45 co-purified with the tight junction protein, ZO-1. Immunofluorescence studies of ROS/Cx45 cells simultaneously stained with polyclonal Cx45 antibody and a monoclonal ZO-1 antibody showed that Cx45 and ZO-1 colocalized in ROS/Cx45 cells. Furthermore we found that ZO-1 could bind to peptides derived from the carboxyl terminal of Cx45 that had been covalently bound to an agarose resin. These data suggests that Cx45 and ZO-1 directly interact in ROS/Cx45 cells.

Microwave hyperthermia for brain tumors.

Twelve patients with malignant brain tumors who had failed to respond to conventional therapies were treated with thermotherapy. Hyperthermic temperatures (approximately 43 degrees C) were induced in the tumors using microwaves at a frequency of 2450 MHz that were guided into the tumors by one or more semirigid coaxial applicators. These applicators fit into 16 gauge tubes or needles and can be inserted into the brain with minimal damage to healthy tissues. During each treatment, the tumors were maintained at hyperthermic temperatures for 1 hour. Several treatments spaced a few days apart were usually administered. The procedure used for producing hyperthermia in brain tumors with microwaves proved to be safe and could be repeated several times without producing toxic effects. Objective tumor responses were obtained in 75% of the patients (decrease in tumor size, 3 patients; slowing of tumor growth, 2 patients; necrosis of tumor tissues verified by pathological examination, 4 patients). Favorable clinical responses were observed in 75% of the patients (rapid decrease in intractable headaches, 5 patients; improvements in clinical deficits, 4 patients). Also, in all patients, the microwave power required to heat for a given time or a given volume decreased during most of the thermotherapy sessions, possibly because of heat damage to the tumor vasculature. Our results, taken together with the results of other investigators, indicate that thermotherapy is a promising modality for treating malignant brain tumors, either as the sole therapy or in combination with radiotherapy and chemotherapy. The next logical steps would be Phase I/II type trials of subjects whose disease is less advanced than the disease of patients treated in the current series of investigations.

Proliferation rates in human malignant melanoma: relationship to clinicopathological features and outcome.

This prospective study investigated the clinical significance of cell kinetics, measured using bromodeoxyuridine injection and flow cytometry, in primary and metastatic cutaneous malignant melanoma. The findings illustrate that melanoma is a relatively slowly proliferating tumour, with a median potential doubling time (T(pot)) of 8.6 days. There were no significant differences in cell kinetics between primary and secondary disease. Both the duration of the S phase (T(s)) and T(pot), but not the labelling index (LI), showed a correlation with some of the main clinicopathological features in primary disease, including Breslow thickness. On univariate analysis, a short T(pot) and a high LI were associated with shorter disease-free intervals and overall survival for metastatic but not primary lesions. On multivariate analysis, these parameters retained significance when analysed separately with the main clinicopathological variables. These findings suggest that assessment of proliferation in melanoma is able to refine the available prognostic information and identify patients with a poor clinical outcome.

Gap junction proteins exhibit early and specific expression during intramembranous bone formation in the developing chick mandible.

The spatial and temporal expression of three closely related members of the connexin family of gap junction proteins (connexin42, Cx42; connexin43, Cx43; and connexin45, Cx45) was evaluated during bone formation in the mandibular process of the chick embryo. Mandibles of chick embryos from Hamburger and Hamilton stage 25 (approximately 5 days) through 19 days of development were dissected, serially sectioned and processed for immunocytochemical localization, employing site-specific anti-connexin antibodies. Our data revealed that (1) Cx43 was present throughout mandibular bone formation; (2) although it appeared to be associated with all bone cell types, Cx43 was concentrated in mesenchymal cells during the earliest stages in the osteogenic lineage; (3) most importantly, the localization of Cx43 at sites of bone formation appeared to precede the overt expression of the osteogenic phenotype; (4) by contrast, Cx45 was more restricted, spatially and temporally, in its distribution; (5) Cx42 expression was not detected in osteogenic tissue during mandibular bone formation. From all of the data obtained, Cx45 appeared to be associated with stages of bone formation characterized by the elaboration of matrix and the progressive expression of the differentiated osteogenic phenotype. Cx43 appeared to be associated with condensation of mesenchyme and the earliest stages of osteogenesis. Because of these associations, we propose that connexin expression may be necessary for the initiation of bone formation and the full expression of the osteogenic phenotype.

Microwave hyperthermia radiosensitized iridium-192 for recurrent brain malignancy.

Twenty-one patients whose solitary detectable biopsy proven recurrent brain malignancies produced Central Nervous System (CNS) symptoms warranting further intervention received 60-minute 43 degrees C (180 degree-minute) interstitial 2450 MHz microwave hyperthermia fractions. All received brain teletherapy prior to recurrence. The first 15 received no brachytherapy and served as a toxicity pilot. All 15 enjoyed neurologic improvement, 12 symptomatic improvement, and 12 objective response as mass reduction and/or tumor necrosis. The next 6 patients were selected with more favorable Karnofsky performance status, no known active malignancy elsewhere, and received afterloading Ir-192 interstitial implantation juxtaposed to radiosensitizing hyperthermia. Volume dose varied from 1000 to 2245 rad, and dose rate from 40 to 100 rad/hr. Dose selected varied as a function of pre-recurrence teletherapy dose, general condition, histologic type, and volume. Neurosurgical debulking, if technically indicated through no additional aperture or trauma, was permitted if consistent with preservation of neurological function. Six enjoyed neurologic improvement, symptom reduction, and objective tumor response; three remain alive, and one experienced transient improvement. Complications, histologic subtypes, autopsy findings, stereotactic approach, thermal monitoring methods and CT follow-up of objective response are presented along with computer dosimetry and isotherm chart. Our microtraumatic universal catheter technique for CT guided stereotactic biopsy, aspiration, decompression, thermal sensory loop, thermalization antennae, and brachytherapy without multiple trauma nor changing catheters is stressed. The rationale for combined modes peculiar to the CNS will be outlined.2+ Proposal for incorporating controlled-release ARA-C chemotherapy polymer micro-rods into the interstitial format will be offered. The preceeding is an FDA-approved controlled clinical trial.(ABSTRACT TRUNCATED AT 250 WORDS)

A burn formula in clinical practice.

In a retrospective review of the 10-year period 1969-78 the intravenous plasma loads given to patients admitted to one burn centre were studied and compared with the volumes predicted by the formula used at that centre. Of 1728 patients admitted 342 (19.8%) received intravenous resuscitation with plasma. The formula appeared to be a good empirical guide to transfusion needs in the 36 h after burning. Patients with burns in excess of 45% body surface area (BSA), and particularly children, were likely to require more fluid than that indicated by the formula estimate. However, as burns in excess of 50% BSA are uncommon (50/1728 admissions) it seems reasonable to use a formula which is a guide to the probable needs of most patients while accepting the clinical response as the best means of assessing the actual fluid need of each patient, especially those with extensive injury.

Assessment of burn injury in the accident and emergency department: a review of 100 referrals to a regional burns unit.

Accurate assessment of the extent of thermal injury in the accident and emergency (A&E) department is essential if appropriate resuscitation and referral to a specialist unit is to occur. However, review of 100 referrals to a regional burns unit confirms that assessment is often inaccurate, and usually undertaken by no one more senior than a casualty officer, leading to suboptimal treatment and referral. Severe thermal injury should be assessed by a team of senior doctors, according to the major trauma protocol, and casualty officers should receive better training in the assessment of less extensive burns.

A clinical study of hyperuricaemic men.

A group of 43 hyperuricaemic men discovered during the 1967 Rangiora diabetic and metabolic survey was examined clinically in 1968 and their blood chemistry repeated. They were then compared with a control group matched for age. No significant differences were found in the two groups either in physical findings or in biochemical measurements apart from the known differences in serum uric acid and the presence of gout in hyperuricaemics. When the study was repeated on the same group in 1973 still no significant difference was found which could be attributed to the hyperuricaemia.