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Biomedical subjects

D Hersh

Publications and source records attributed to D Hersh.

17 recordsLinked to original sources
PubMed2006

Patterns of regional head and neck lymph node metastasis in primary conjunctival malignant melanoma.

OBJECTIVE: To correlate patterns of regional lymph node metastasis with the site of origin in primary conjunctival malignant melanoma. DESIGN: Retrospective analysis (1990-2003) of clinical data. SETTING: Two London tertiary referral centres. PARTICIPANTS: 12 patients presenting with regional metastases after failed local treatment for conjunctival malignant melanoma. RESULTS: 6 cases predominantly involving the temporal conjunctiva metastasised to the pre-auricular lymph nodes. Two cases predominantly involving the nasal conjunctiva metastasised to the submandibular nodes. Of the two cases with purely multifocal disease, one metastasised to the pre-auricular nodes and another to both submandibular and parotid nodes. One primary conjunctival malignant melanoma had its origin in temporal conjunctiva but metastasised to submandibular nodes, and another case originating from nasal conjunctiva metastasised to pre-auricular nodes. CONCLUSIONS: Temporal conjunctival melanotic lesions tend to metastasise clinically to pre-auricular lymph nodes and nasal conjunctival melanotic lesions metastasise to the submandibular lymph nodes. Patterns appear consistent with laboratory-based anatomically mapped lymphatic drainage basins of the conjunctiva.

Adult↗
PubMed2001

Structure-function analysis of the Shigella virulence factor IpaB.

Infection by the gram-negative bacterium Shigella flexneri results in dysentery, an acute inflammatory disease of the colon. Essential events in the pathogenesis of Shigella infections include bacterial invasion of epithelial cells, escape from the phagosome, and induction of apoptosis in macrophages. The Shigella virulence factor invasion plasmid antigen B (IpaB) is required for all of these processes. Induction of apoptosis is dependent on IpaB binding to the cysteine protease caspase-1 (Casp-1). The activation of this enzyme triggers both apoptosis and release of the proinflammatory cytokine interleukin-1beta. Several IpaB mutants were generated to correlate function with protein subdomains. We determined that the N-terminal portion of IpaB is necessary for stable expression of IpaB. A putative amphipathic alpha-helical domain preserves the structure of IpaB. We found 10 consecutive residues within the amino terminus of the hydrophobic region that play a critical role in invasion, phagosomal escape, and cytotoxicity. An IpaB mutant carrying a mutation in this region binds to Casp-1 yet is not cytotoxic, even following direct delivery to the macrophage cytoplasm. These results indicate that the association between IpaB and Casp-1 is only a step in the activation of macrophage apoptosis.

Alanine↗
PubMed2001

Experiences of ending aphasia therapy.

Despite a considerable literature on assessment and treatment issues in aphasiology, little has been written about how therapy ends. We lack detail about how clinicians decide to terminate treatment and about how patients and carers view leaving therapy. This paper explores experiences and perceptions of aphasia treatment termination. It uses in-depth interview data gathered in South Australia as part of a doctoral study with a speech pathologist, three ex-patients with aphasia and one spouse. This case study allows comparison of client and professional narratives to each other and also to the official discharge documentation in the medical file. The discharge process arising from this analysis is discussed.

Aged↗
PubMed2000

Salmonella exploits caspase-1 to colonize Peyer's patches in a murine typhoid model.

Salmonella typhimurium invades host macrophages and induces apoptosis and the release of mature proinflammatory cytokines. SipB, a protein translocated by Salmonella into the cytoplasm of macrophages, is required for activation of Caspase-1 (Casp-1, an interleukin [IL]-1beta-converting enzyme), which is a member of a family of cysteine proteases that induce apoptosis in mammalian cells. Casp-1 is unique among caspases because it also directly cleaves the proinflammatory cytokines IL-1beta and IL-18 to produce bioactive cytokines. We show here that mice lacking Casp-1 (casp-1(-/)- mice) had an oral S. typhimurium 50% lethal dose (LD(50)) that was 1,000-fold higher than that of wild-type mice. Salmonella breached the M cell barrier of casp-1(-/)- mice efficiently; however, there was a decrease in the number of apoptotic cells, intracellular bacteria, and the recruitment of polymorphonuclear lymphocytes in the Peyer's patches (PP) as compared with wild-type mice. Furthermore, Salmonella did not disseminate systemically in the majority of casp-1(-/)- mice, as demonstrated by significantly less colonization in the PP, mesenteric lymph nodes, and spleens of casp-1(-/)- mice after an oral dose of S. typhimurium that was 100-fold higher than the LD(50). The increased resistance in casp-1(-/)- animals appears specific for Salmonella infection since these mice were susceptible to colonization by another enteric pathogen, Yersinia pseudotuberculosis, which normally invades the PP. These results show that Casp-1, which is both proapoptotic and proinflammatory, is essential for S. typhimurium to efficiently colonize the cecum and PP and subsequently cause systemic typhoid-like disease in mice.

Animals↗
PubMed1999

The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1.

Recently, Salmonella spp. were shown to induce apoptosis in infected macrophages. The mechanism responsible for this process is unknown. In this report, we establish that the Inv-Spa type III secretion apparatus target invasin SipB is necessary and sufficient for the induction of apoptosis. Purified SipB microinjected into macrophages led to cell death. Binding studies show that SipB associates with the proapoptotic protease caspase-1. This interaction results in the activation of caspase-1, as seen in its proteolytic maturation and the processing of its substrate interleukin-1beta. Caspase-1 activity is essential for the cytotoxicity. Functional inhibition of caspase-1 activity by acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone blocks macrophage cytotoxicity, and macrophages lacking caspase-1 are not susceptible to Salmonella-induced apoptosis. Taken together, the data demonstrate that SipB functions as an analog of the Shigella invasin IpaB.

Animals↗
PubMed1999

The validity of self-reported cocaine use in two groups of cocaine abusers.

To evaluate the validity of 2 self-report methods for estimating cocaine use, Timeline Follow-Back (TLFB) and weekly calendar reports from 65 patients with a cocaine use disorder were compared with urine drug test results. The TLFB showed fair to moderate validity, and the weekly calendar showed moderate to high validity in measuring the frequency of cocaine use. Similar results were obtained when the self-report measures were used to time specific cocaine use episodes. In addition to evidence for superiority of the weekly calendar, the validity of self-reports was inversely related to the percentage of positive urine test results. Furthermore, there was some evidence that validity increased as the time window over which the comparisons were drawn increased. Given the central role of self-reports in the clinical and research evaluation of drug use, factors affecting their validity warrant further investigation.

Adult↗
PubMed1998

Shigella-induced apoptosis is dependent on caspase-1 which binds to IpaB.

We report here that the Shigella invasion plasmid antigen (Ipa)B, which is sufficient to induce apoptosis in macrophages, binds to caspase (Casp)-1, but not to Casp-2 or Casp-3. Casp-1 is activated and its specific substrate interleukin-1beta is cleaved shortly after Shigella infection. Macrophages isolated from Casp-1 knock-out mice are not susceptible to Shigella-induced apoptosis, although they respond normally to other apoptotic stimuli. Shigella kills macrophages from casp-3, casp-11, and p53 knock-out mice as well as macrophages overexpressing Bcl-2. We propose that Shigella induces apoptosis by directly activating Casp-1 through IpaB, bypassing signal transduction events and caspases upstream of Casp-1. Taken together these data indicate that Shigella-induced apoptosis is distinct from other forms of apoptosis and seems uniquely dependent on Casp-1.

Animals↗
PubMed1998

Naltrexone treatment of comorbid alcohol and cocaine use disorders.

Naltrexone (NTX) has been shown to be efficacious for the treatment of alcohol dependence. Since alcohol and cocaine use disorders commonly co-occur, we conducted a randomized, double-blind, placebo-controlled trial of NTX 50 mg/day in 64 subjects with comorbid alcohol and cocaine use disorders. Although subjects in both groups reduced their consumption of both alcohol and cocaine during the 8-week trial, there was no consistent advantage to NTX over placebo treatment. We conclude that, due to behavioral, neurochemical, or other factors, individuals with both alcohol and cocaine use disorders are distinct from those dependent on alcohol alone, and that NTX at a dosage of 50 mg/day is not efficacious in this patient population. Several factors, including medication dosage, length of treatment, sample size and attrition rate, limit the interpretation of these findings. Consequently, we recommend that subsequent trials of NTX to reduce the risk of relapse in patients with comorbid alcohol and cocaine use disorders take these issues into account.

Adult↗
PubMed1998

How bacteria initiate inflammation: aspects of the emerging story.

Recent studies have shown that bacteria possess an array of proinflammatory molecules in addition to the extensively studied lipopolysaccharide and superantigens. These bacterial molecules include soluble and membrane-associated inducers of cytokine release, inducers of host cell apoptosis, and immunostimulatory DNA. There is therefore much greater diversity in the class of molecules and mechanisms by which bacteria engage the host immune system than previously appreciated.

Apoptosis↗
PubMed1997

Effects of naltrexone on cue-elicited craving for alcohol and cocaine.

This study examined the effects of naltrexone (50 mg/day) on mood and self-reported desire for alcohol and cocaine in 26 patients with comorbid alcohol and cocaine abuse/dependence. Two laboratory sessions were conducted, separated by 1 week. During the sessions, subjects viewed 5-min films containing either cocaine, alcohol, or neutral cues. The first session occurred prior to random assignment to medication group and the second session was held after 1 week of double-blind treatment with either naltrexone or placebo. The cocaine-related film induced a greater desire to use cocaine than the desire for alcohol that was induced by the alcohol-related film. This finding was observed using both a simple, one-item analog scale administered during the films and more complex craving questionnaires administered immediately after the films. Collectively, the alcohol and cocaine-related films evoked greater levels of self-reported anxiety and elation, and lower levels of concentration, than the neutral film. Naltrexone did not differ from placebo in reducing the desire to use either cocaine or alcohol.

Adolescent↗
PubMed1996

The in vitro generation of post-Golgi vesicles carrying viral envelope glycoproteins requires an ARF-like GTP-binding protein and a protein kinase C associated with the Golgi apparatus.

We have developed a system that recreates in vitro the generation of post-Golgi vesicles from an isolated Golgi fraction prepared from vesicular stomatitis virus- or influenza virus-infected Madin-Darby canine kidney or HepG2 cells. In this system, vesicle generation is temperature- and ATP-dependent and requires a supply of cytosolic proteins, including an N-ethylmaleimide-sensitive factor distinct from NSF. Cytosolic proteins obtained from yeast were as effective as mammalian cytosolic proteins in supporting vesicle formation and had the same requirements. The vesicles produced (50-80 nm in diameter) are depleted of the trans Golgi marker sialyltransferase, contain the viral glycoprotein molecules with their cytoplasmic tails exposed, and do not show an easily recognizable protein coat. Vesicle generation was inhibited by brefeldin A, which indicates that it requires the activation of an Arf-like GTP-binding protein that promotes assembly of a vesicle coat. Vesicles formed in the presence of the nonhydrolyzable GTP analogue guanosine 5'-3-O-(thio)triphosphate retained a nonclathrin protein coat resembling that of COP-coated vesicles, and sedimented more rapidly in a sucrose gradient than the uncoated ones generated in its absence. This indicates that GTP hydrolysis is not required for vesicle generation but that it is for vesicle uncoating. The activity of a Golgi-associated protein kinase C (PKC) was found to be necessary for the release of post-Golgi vesicles, as indicated by the capacity of a variety of inhibitors and antibodies to PKC to suppress it, as well as by the stimulatory effect of the PKC activator 12-O-tetradecanoylphorbol-13-acetate.

ADP-Ribosylation Factors↗
PubMed1995

Carbamazepine treatment of cocaine dependence: a placebo-controlled trial.

Cocaine-induced kindling, which has been hypothesized to underlie cocaine-induced craving, is reversed by carbamazepine treatment. Though preliminary studies showed carbamazepine to be useful for relapse prevention in cocaine-dependent subjects, more recent studies have failed to replicate those findings. We conducted a randomized, double-blind, placebo-controlled trial of carbamazepine 600 mg/day in 40 cocaine-dependent males. During active treatment there were no significant effects of carbamazepine on cocaine use, alcohol consumption, anxiety or depressive symptoms. At three months post-treatment carbamazepine-treated subjects reported fewer drinking days. We conclude that carbamazepine at this dose level is probably not efficacious for treatment of cocaine dependence.

Adolescent↗
PubMed1995

Carbamazepine and cocaine-cue reactivity.

Subjective and electroencephalographic reactions to cocaine cues were evaluated in 33 cocaine-dependent out-patients and 17 non-cocaine-dependent controls. Subjective, EEG, and autonomic reactions to three 5-min videos (cocaine-associated, erotic, neutral) were evaluated twice with an interpolated 1-week interval. Between evaluations, cocaine-dependent patients received carbamazepine 400 mg daily or matching placebo in double-blind fashion. In all three groups the cocaine-associated and erotic videos produced a comparable increase in the self-rated desire for cocaine and reduction in total EG power. Carbamazepine treatment increased EEG fast alpha power and self-rated fatigue, and decreased self-rated concentration and vigor. However, it had no specific effect on subjective or physiological reactivity to either the cocaine-associated or erotic videos. This negative finding is consistent with recent clinical trials of carbamazepine for cocaine dependence.

Adolescent↗