Tuberculosis retreatment category predicts resistance in hospitalized retreatment patients in a high HIV prevalence area.

SETTING: Rates of multidrug-resistant tuberculosis (MDR-TB) are currently as high as 7.7% in retreatment cases in KwaZulu-Natal, South Africa. MDR-TB prevalence is known to be high in patients categorized as treatment failures. Recent reports have questioned the effectiveness of the World Health Organization (WHO) Category II regimen in retreatment TB cases. OBJECTIVE: To determine whether treatment category predicts susceptibility patterns and outcomes in a hospitalized population of retreatment TB cases. DESIGN: Retrospective cohort of 197 pulmonary retreatment cases. RESULTS: Retreatment cases treated with the standard retreatment regimen had a high in-hospital mortality (19.8%), or poor outcome (26.4%) and a high rate of MDR-TB (16.2%). The 'treatment failure' category predicted resistance, with 57.1% of patients exhibiting any resistance compared to other treatment categories (P = 0.02); 53.8% of patients with any resistance experienced poor outcomes, compared to 16.6% of pan-susceptible cases (P = 0.02). There was a trend towards poor outcome in the treatment failure category (42.9%, P = 0.13). CONCLUSION: The retreatment category 'treatment failure' is associated with a high prevalence of resistance in an area of high human immunodeficiency virus (HIV) prevalence. The 'treatment failure' category should be used to identify patients who may benefit from alternative regimens using directed, intensified therapy or second-line agents instead of the current standard retreatment regimen.

An ICT solution for community mental health--putting virtuality into the vision.

The digital age has brought about revolutionary changes in the capacity and methods of managing information. There has been an evolutionary pathway leading from information technology through informatics to communication technology. The 'nineties' has been a decade of patient empowerment fuelled by Internet access and legal rights to information. Clinicians as a whole have lagged in their adoption of the new technologies. Mental health has been seen as a particularly difficult domain because of its multi-professional and multi-locational patterns of service delivery and its traditional reliance upon narrative in the absence of bio-pathologic data. The Hospitaller Order of St John of God has been facing these challenges. The authors describe an integrated information/communication technology (ICT) which can be provided on the clinician's desktop and show that the new integrated ICT affords new opportunities for addressing the needs of community-based mental health services.

Inhibition of secretion by 1,3-Cyclohexanebis(methylamine), a dibasic compound that interferes with coatomer function.

We noted previously that certain aminoglycoside antibiotics inhibit the binding of coatomer to Golgi membranes in vitro. The inhibition is mediated in part by two primary amino groups present at the 1 and 3 positions of the 2-deoxystreptamine moiety of the antibiotics. These two amines appear to mimic the epsilon-amino groups present in the two lysine residues of the KKXX motif that is known to bind coatomer. Here we report the effects of 1, 3-cyclohexanebis(methylamine) (CBM) on secretion in vivo, a compound chosen for study because it contains primary amino groups that resemble those in 2-deoxystreptamine and it should penetrate lipid bilayers more readily than antibiotics. CBM inhibited coatomer binding to Golgi membranes in vitro and in vivo and inhibited secretion by intact cells. Despite depressed binding of coatomer in vivo, the Golgi complex retained its characteristic perinuclear location in the presence of CBM and did not fuse with the endoplasmic reticulum (ER). Transport from the ER to the Golgi was also not blocked by CBM. These data suggest that a full complement of coat protein I (COPI) on membranes is not critical for maintenance of Golgi integrity or for traffic from the ER to the Golgi but is necessary for transport through the Golgi to the plasma membrane.

Finding ethical principles and practical guidelines for the controlled flow of patient data.

The application of computing to health care, and particularly to electronic patient records, offers major benefits but raises issues of confidentiality and of potential misuse. Sound access control mechanisms are therefore important, but most models focus upon informed consent by the data subject. This raises challenges in mental health care, and for other vulnerable patients including those comatose, and the severely ill and temporarily distressed. Published algorithms which are used to control record access within a controlled environment therefore have value, as a means of ensuring an open and informed, yet ethically sound, solution. The paper describes the background and issues, and gives an example of such an algorithm.

From bridges to super-highways: transmitting meaning within and between professions, and across time and space--beginning the process.

As development of health informatics, including electronic patient records, proceeds apace there is an innate tendency to focus on acute and primary care, and upon bio-pathological data sets. This is where virtually all research and investment is being directed. However, the core purpose of health care (and mental health care in particular) is to improve and maintain the individual's functioning and sense of well-being, not simply to eliminate adverse pathology. It is therefore vital for health care records to contain subjective, descriptive, and self-expressed components if the record is to have true health meaning. This in turn raises challenges about meaning and context, terms and language. Most informatic systems run the risk of being Islands of Automation, linked at best by bridges conveying data sets rather than knowledge. If health informatics is really to serve people and their health, attention needs to be given to developing the recording, communication, and understanding of perception through shared meaning. Only then will informatics systems be full supporters of the people's health, and record system linkages become Super-Highways of Knowledge between patients and their supporting professionals.

Use of losartan in the treatment of hypertensive patients with a history of cough induced by angiotensin-converting enzyme inhibitors.

The objective of this study was to determine the incidence of dry cough in hypertensive patients with a history of angiotensin-converting enzyme (ACE) inhibitor-induced cough after treatment with losartan (an angiotensin II-receptor antagonist), lisinopril (an ACE inhibitor), or placebo. One hundred patients from 16 outpatient treatment centers in the United States were included in this double-masked, randomized, parallel-group, active- and placebo-controlled study, with stratification according to sex. After a challenge phase with lisinopril and a placebo washout phase, patients were randomly allocated to receive losartan 50 mg once daily, lisinopril 20 mg once daily, or placebo for a maximum of 8 weeks. The primary efficacy end point of the study was the presence or absence of dry cough during the double-masked period, as rated by the patient at each visit using a validated symptom assessment questionnaire. A secondary end point was the frequency of dry cough, as measured at each visit using a visual analogue scale (VAS). The incidence of dry cough was significantly higher in the lisinopril group than in the losartan and placebo groups (87.5% vs 36.7% and 31.4%, respectively) at the end of the double-masked treatment period; there was no statistically significant difference between the losartan and placebo groups. Mean VAS scores showed that patients treated with lisinopril rated themselves as having a significantly higher frequency of cough than did patients treated with losartan or placebo (4.0 vs 1.2 and 1.5, respectively). Again, the difference between the losartan and placebo groups was not statistically significant. All treatments were otherwise well tolerated, and no serious clinical or laboratory adverse events were reported during the double-masked phase of the study. These results demonstrate that the incidence, severity, and frequency of dry cough in patients with a history of ACE inhibitor-induced dry cough are significantly lower in those treated with losartan than in those treated with lisinopril and are similar to the incidence, severity, and frequency of dry cough in those receiving placebo.

An unusual dienone-phenol rearrangement product formed during the synthesis of mometasone furoate (Sch 32088).

The structure of an unusual dienone-phenol rearrangement product 4 obtained during the synthesis of mometasone furoate (Sch 32088) was assigned on the basis of NMR and x-ray crystallographic data. The mechanism of formation is discussed.

The electronic patient record as a guarantor of personalised mental health care.

A provider of mental health services on multiple sites experienced major problems of availability with traditional paper records and commenced development of an electronic patient record (EPR) and clinical information system in order to provide integrated, real time patient based information. The development process, including clinical and technical considerata is described in order to draw conclusions about the ways in which EPR's can be a vehicle for change from traditional practice to the multidisciplinary, community based practise developments of recent years. The system can generate information for continuous quality improvement, service planning, and philosophies of care. The key requirements of good record systems are established and the inability of paper records to meet them. In contrast the electronic record has demonstrated ability to guarantee personalised, quality, mental health care.

Towards an ethical protocol in mental health informatics.

Application of informatics to mental health has the potential to benefit a disadvantaged yet important patient group. At the same time, difficult issues are raised with regard to data protection and ethics because many patients are not able to express informed and rational views, and this increases their vulnerability. However, developments in this field are limited, and there is little literature. Generic data protection legislation and guidance assumes that data subjects are mentally competent adults. This paper distils key ethical issues and principles in mental health informatics, and describes a process which has initiated the identification of "reasonable" practice.

Interaction of coatomer with aminoglycoside antibiotics: evidence that coatomer has at least two dilysine binding sites.

Coatomer is the soluble precursor of the COPI coat (coat protein I) involved in traffic among membranes of the endoplasmic reticulum and the Golgi apparatus. We report herein that neomycin precipitates coatomer from cell extracts and from purified coatomer preparations. Precipitation first increased and then decreased as the neomycin concentration increased, analogous to the precipitation of a polyvalent antigen by divalent antibodies. This suggested that neomycin cross-linked coatomer into large aggregates and implies that coatomer has two or more binding sites for neomycin. A variety of other aminoglycoside antibiotics precipitated coatomer, or if they did not precipitate, they interfered with the ability of neomycin to precipitate. Coatomer is know to interact with a motif (KKXX) containing adjacent lysine residues at the carboxyl terminus of the cytoplasmic domains of some membrane proteins resident in the endoplasmic reticulum. All of the antibiotics that interacted with coatomer contain at least two close amino groups, suggesting that the antibiotics might be interacting with the di-lysine binding site of coatomer. Consistent with this idea, di-lysine itself blocked the interaction of antibiotics with coatomer. Moreover, di-lysine and antibiotics each blocked the coating of Golgi membranes by coatomer. These data suggest that certain aminoglycoside antibiotics interact with di-lysine binding sites on coatomer and that coatomer contains at least two of these di-lysine binding sites.

Elevation of vacuolar pH inhibits the cytotoxic activity of furin-cleaved exotoxin A.

Exotoxin A (ETA) inhibits protein synthesis in cells by a process that involves receptor-mediated endocytosis and the transport of a 37-kDa proteolytic fragment across a membrane into the cytoplasm. The fragment is apparently generated by the endoprotease furin after the toxin has been endocytosed. Cleavage of ETA by furin requires a low pH in vitro, and presumably also in vivo. Drugs that raise the pH of intracellular compartments are known to protect cells from ETA. The simplest hypothesis to explain this protection has been that the drugs interfere with furin cleavage. To test this idea, we measured the effect of pH-elevating drugs on the action of ETA that had been precleaved with recombinant furin before addition to cells. Surprisingly, we found that pH-elevating drugs protected cells from precleaved ETA as well as intact ETA. These results suggest that the process by which ETA intoxicates cells requires a low vacuolar pH for another event in addition to proteolysis by furin.

Urinary creatine as a potential marker of testicular damage: effect of vasectomy.

The concentrations of creatine in the rat testis are high compared to all other tissues except muscle. The total creatine content of the testis is also considerably greater than all organs examined except muscle. Vasectomised male rats were given 2-methoxyethanol or cadmium chloride at doses that caused testicular damage. In the vasectomised rats, testicular damage still resulted in significant creatinuria. This indicates the creatine reaches the urine at least partly via the blood stream and not via the vas deferens.

Comparison of urinary creatine with other biomarkers for the detection of 2-methoxyethanol-induced testicular damage.

Abstract This study has compared different biomarkers of testicular damage, in particular evaluating urinary creatine as a non-invasive marker. Male rats were exposed to various doses of 2-methoxyethanol, a known testicular toxicant. Pathological damage, testis weight, urinary creatine and creatinine, serum lactate dehydrogenase, isozyme C4 (LDH-C4), and serum testosterone were determined. 2-Methoxyethanol caused dose-dependent pathological damage to the testes which was detectable at the lowest dose (100 mg kg(-1)). Urinary creatine excretion was significantly raised at all doses but testis weight was only significantly decreased at the highest two doses (500, 750 mg kg(-1)). Serum testosterone was only significantly decreased at 500 mg kg(-1) and LDH-C4 was not significantly increased at any dose. Therefore urinary creatine was the most sensitive marker of 2-methoxethanol-induced testicular damage and dysfunction.

Suicide among psychiatric hospital in-patients.

We examined for risk factors for suicide among psychiatric in-patients by comparing 37 in-patients from an Ontario Provincial Psychiatric Hospital who had committed suicide with 37 age and sex matched in-patient controls. Significantly more of the suicide victims had made a previous suicide attempt (62.2 v. 35.1%), suffered from schizophrenia (75.7 v. 35.1%), were involuntary at their last admission (70.3 v. 43.2%) and lived alone (70.3 v. 43.2%). Only six patients committed suicide on the ward. Almost a third of the patients, the majority schizophrenic, committed suicide after having been in the hospital for more than a year. These results suggest that in the psychiatric hospital setting the in-patient at risk for suicide has previously exhibited suicidal behaviour, suffers from schizophrenia, was admitted involuntarily, lives alone and that the risk of suicide may remain high among long-stay schizophrenics.

Studies on the muscle toxicant 2,3,5,6-tetramethyl p-phenylenediamine: effects on various biomarkers including urinary creatine and taurine.

The effect of the specific muscle toxicant, 2,3,5,6-tetramethyl p-phenylenediamine (TMPD), on urinary creatine and taurine, markers of testicular and liver dysfunction, respectively, has been investigated in male Sprague-Dawley rats. Damage to the gastrocnemius and soleus muscles was accompanied by a rise in serum creatine kinase (predominantly the muscle-specific isoenzyme, CK-MM), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Increases in serum alpha-hydroxybutyrate dehydrogenase (HBDH) and total lactate dehydrogenase (LDH) (mainly isoenzymes, LDH1 and LDH2), occurred but only minor damage to the heart and no rise in CK-MB, (heart muscle isoenzyme) was seen. Damage to stage XIV tubules in the testis was evident histologically after the highest dose. This was accompanied by an increase in LDH-C4 testis-specific isoenzyme and a decrease in serum testosterone. Apart from reduced serum albumin, no other serum parameters indicated liver damage and there was only slight liver steatosis in some animals at the highest dose. Urinary taurine was not significantly raised after any dose of TMPD, but there was a significant increase in urinary creatine after the highest dose. It can be concluded that in the presence of discrete muscle damage, the use of urinary taurine and urinary creatine as markers of liver and testicular dysfunction, respectively, is not confounded. However, a variety of different markers should be used in conjunction to fully delineate the tissue damage due to toxic chemicals.

The nature of major histocompatibility complex recognition by gamma delta T cells.

Despite intensive efforts, the general rules for gamma delta T cell recognition remain undefined. Here, we take advantage of the detailed knowledge of the molecular structure and biosynthetic pathways of major histocompatibility complex (MHC) molecules to analyze the recognition properties of the gamma delta T cell clones LBK5 (specific for the class II MHC, IEk) and G8 (specific for the nonclassical class I MHC, TL10b). We find that the activation of these clones requires neither class I nor class II antigen-processing and that peptides do not confer specificity. Epitope mapping also shows that the topology of gamma delta T cell receptor interaction with the MHC is distinct from that of alpha beta T cells. These results suggest that the molecular nature of gamma delta T cell recognition is fundamentally different than that of alpha beta T cells.