Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis.

Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin. PZA is a pro-drug of pyrazinoic acid (POA) (ref. 3), whose target of action has never been identified. Although PZA is active only against Mycobacterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-Cl-PZA) displays a broader range of anti-mycobacterial activity. We have found that the eukaryotic-like fas1 gene (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-Cl-PZA when present on multi-copy vectors in M. smegmatis. 5-Cl-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C24/C26 fatty acids from acetyl-CoA (ref. 6). Importantly, PZA inhibited FASI in M. tuberculosis in correlation with PZA susceptibility. These results indicate that FASI is a primary target of action for PZA in M. tuberculosis. Further characterization of FASI as a drug target for PZA may allow the development of new drugs to shorten the therapy against M. tuberculosis and may provide more options for treatment against M. bovis, M. avium and drug resistant M. tuberculosis.

The unfolded-protein-response pathway in yeast.

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers the increased production of several ER-resident proteins. This signalling pathway exists in organisms as divergent as mammals and yeast, and is the only known example of an intracellular signalling system that links the ER and the nucleus. Recently, a transmembrane kinase similar in structure to growth-factor receptor kinases has been identified as a key component of the unfolded-protein-response pathway in yeast.

Formation Constants and Conformational Analysis of Carbamates in Aqueous Solutions of 2-Methylpiperidine and CO2 from 283 to 313 K by NMR Spectroscopy.

Quantitative 13C nuclear magnetic resonance (NMR) spectroscopy was used to investigate the speciation in (2-methylpiperidine + H2O + CO2) systems at 283.2-313.2 K. The carbamate of 2-methylpiperidine(2-methylpiperidine- N-carboxylate) was shown for the first time to be a stable species in aqueous solutions. The spectroscopic results were used to obtain temperature-dependant formation constants for the carbamate using a simplified model for the activity coefficients from which the standard molar enthalpy of reaction was estimated. The results were incorporated into a self-consistent chemical equilibrium model, which includes vapor-liquid equilibria and all aqueous species, including the formation of carbamate. The predominant conformation of the sterically hindered carbamate, which was determined using two-dimensional exchange spectroscopy NMR, has the methyl group in the axial orientation and is in agreement with the density functional theory quantum chemical calculations.

The unfolded protein response coordinates the production of endoplasmic reticulum protein and endoplasmic reticulum membrane.

The endoplasmic reticulum (ER) is a multifunctional organelle responsible for production of both lumenal and membrane components of secretory pathway compartments. Secretory proteins are folded, processed, and sorted in the ER lumen and lipid synthesis occurs on the ER membrane itself. In the yeast Saccharomyces cerevisiae, synthesis of ER components is highly regulated: the ER-resident proteins by the unfolded protein response and membrane lipid synthesis by the inositol response. We demonstrate that these two responses are intimately linked, forming different branches of the same pathway. Furthermore, we present evidence indicating that this coordinate regulation plays a role in ER biogenesis.

Lumbar magnetic resonance imaging findings in patients with and without Waddell Signs.

BACKGROUND CONTEXT: Waddell Signs (WS), introduced as a method to establish patients with substantial psychosocial components to their low back pain, carry a negative association despite no literature evaluating whether physical disease is associated with them. PURPOSE: To compare lumbar magnetic resonance imaging (MRI) findings between the patients with and without WS. STUDY DESIGN: Retrospective cohort study based on prospectively collected data. PATIENT SAMPLE: Thirty patients aged 35 to 55 years with an Oswestry Disability Index (ODI) score >50 randomly selected such that there was an even distribution of patients based on the number of WS. OUTCOME MEASURES: ODI and Short Form-12 scores, number of WS, presence and severity of spinal pathology. METHODS: MRIs were reviewed by three spine specialists blinded to clinical exam findings, number of WS, and patient identity. Type and severity of pathology and presence of surgical and non-surgical lesions were assessed, and findings were rank ordered based on the overall impression of the pathology. There was no external funding or potential conflicts of interest for this study. RESULTS: There were significantly more individual pathologic findings in patients without WS (p=.02). However, there was no difference in the severity of pathology based on WS (p=.46). Furthermore, the rank ordering based on overall impression of severity showed no difference between the patients with and without WS (p=.20). Although 100% of the patients without WS showed pathologic findings on MRI, 70% of WS patients also had significant pathology on MRI. The prevalence of spondylolisthesis, stenosis, and disc herniation was similar (p=.41, p=.22, and p=.43, respectively). The prevalence and mean number of lesion amenable to surgery did not differ based on presence of WS (p=.21 and p=.18, respectively). CONCLUSIONS: Patients with WS present a difficult diagnostic challenge for the physician as their organic symptoms are often coexistent with emotional fear avoidance behavior. Although there is more overall pathology in patients without WS, a significant number of these patients appear to have comparable spinal pathology with equivalent severity, which may be contributing to patients' symptoms and disability. Presence of these non-organic symptoms often makes us doubt these patients. However, as part of effective treatment, physicians should better understand both the physical and psychological components of patient disability.

Long-term outcome of a self-help very-low-calorie-diet weight-loss program.

This paper presents 90-wk data on five seriously overweight subjects originally brought together for 1-2 wk in simple residential accommodation to share the experience of beginning a program of very-low-calorie dieting. All subjects have remained well below their starting weight; four of the five subjects have continued to lose weight (weight losses 33.7-66.8 kg), now weighing less than at the end of the first 26 wk previously reported (1). It is proposed that this self-help group model, incorporating a very-low-calorie diet, is valuable for the long-term management of obesity.

Intravenous iron-dextran: studies on unsaturated iron-binding capacity.

A method is described for measuring the plasma unsaturated iron-binding capacity in the presence of very high concentrations of iron as iron-dextran. The procedure utilizes (59)Fe to label the apotransferrin with subsequent separation of ionic iron from transferrin-bound iron on an ion exchange or Sephadex G.25 column. The unsaturated iron-binding capacity has been measured in rabbits and dogs after intravenous injection of iron-dextran and in human subjects after total dose infusion of iron-dextran. No evidence of saturation of the unsaturated iron-binding capacity was found even when the plasma iron values were greater than 40,000 mug Fe/100 ml.

Environmental fate of rice pesticides in California.

Each of the pesticides reviewed is reported to dissipate from field water after application. Carbofuran is hydrolyzed rapidly under the alkaline conditions usually found in the rice field environment, and its hydrolysis products are also degraded rapidly. The longest half-life reported (18-26 d) was in water that overlaid soil treated with Furadan granular formulation. Generally, carbofuran dissipation ranged from 36 hr to 3 d. Under field application, bensulfuron methyl showed a half-life of 1-3 d, but others have recovered all of the "dissipated" herbicide in the soil compartment. MCPA applied to rice fields is reportedly degraded by the joint action of sunlight and microbial action with a half-life of 3-5 d. Methyl parathion showed a maximum half-life of 9-17 d in a model aquatic ecosystem, but other reports found more rapid dissipation. The half-life of molinate has been observed by numerous researchers to be less than 5 d, with volatility the major route of loss. A half-life as short as 5-7 d has been reported for thiobencarb applied to rice fields, but others report much longer periods; volatility again is expected to be a significant route of loss. Microbial degradation takes place with each of the subject pesticides. Numerous authors have reported enhanced degradation of carbofuran under conditions of repeated application, and this probably holds true for the others. A specialized segment of the microbial population (Pseudomonas spp.) is purported to carry out most of the degradation but is inefficient at degrading the hydrolysis product, carbofuran phenol. Biodegradation of bensulfuron methyl has been observed with actinomycetes, fungi, and bacteria, and takes place primarily by oxidation and hydrolysis. Methyl parathion is biodegraded primarily by nitro reduction to aminomethyl parathion. A fungus, an actinomycete, and a bacterium were shown to biodegrade molinate, primarily by oxidation at the sulfur atom and the azepine ring. Thiobencarb is biodegraded in anaerobic sediments at a slow rate; the dechlorinated thiobencarb was shown to cause dwarfing of rice in some fields. Otherwise, its aerobic biodegradation is rapid and follows the same routes as with molinate. Carbofuran is a systemic insecticide that is rapidly absorbed and translocated to aerial parts of the plant. Carbofuran is metabolized in rice plants to the corresponding phenol, which is irreversibly bound into the plant, as well as to 3-hydroxycarbofuran and other minor components; it is depurated through leaf exudate, from which it volatilizes. Rice plants were observed to take up more bensulfuron methyl through shoots than roots and to metabolize it to the 4-hydroxy analog. The half-life of methyl parathion in Hydrilla verticulla, an aquatic macrophyte, was 1 wk, but little has been reported on methyl parathion in plants. Barnyardgrass was found to absorb greater amounts of molinate than did rice, and it produced larger proportions of basic metabolites, which may form the basis for its selective toxicity. Thiobencarb has been shown to be rapidly absorbed, translocated, and metabolized in rice plants, barnyardgrass, and the broadleaved wild amaranth, smartweed, and lambsquarters. Translocation was more rapid and extensive in barnyardgrass than in rice, and most of the 14C radiolabel was recovered as metabolites. Its terminal metabolite, chlorobenzoic acid, was taken up into lignin-like plant constituents. It is apparent that information on plant uptake and biodegradation is limited--none exists for woody species--but the fact that some species appear resistant to the herbicides suggests that biodegradative ability is general. (ABSTRACT TRUNCATED)

Current concepts in the role of steroids in the treatment of sprains and strains.

With the development of nonsteroidal anti-inflammatory drugs, the use of corticosteroids in the treatment of sprains and strains has greatly diminished. They are used occasionally in the treatment of tendinitis in various areas of the body, but they are not used for ligamentous sprains and muscle strains. Injection of corticosteroids into ligaments, tendons and joints is often quite controversial and most clinicians have abandoned their use in the treatment of common athletic injuries.

Interaction of cromolyn sodium in aqueous solution with magnesium ions.

The interaction of the antiasthmatic drug cromolyn sodium with Mg2+ ions in solution was studied. Selective ion electrode and torsion viscometer measurements were used to establish the degree of interaction. At the concentrations studied, the cromolyn ion had no more affinity for Mg2+ than SO42-. However, thixotropic gels were formed between 4 X 10(-2) M cromolyn sodium and 4 X 10(-4) Mg2+. At lower concentrations of Mg2+, viscosity still increased significantly. However, when the cromolyn concentration was lowered, the increase in viscosity was much less marked.

An evaluation of the Elmslie-Trillat procedure for management of patellar dislocations and subluxations: a preliminary report.

The Elmslie-Trillat procedure involves lateral retinacular release, medial capsular reefing, and medial transposition of the anterior tibial tubercle hinged on a distal periosteal attachment. It is an easily performed procedure and is an excellent method for realignment of the extensor mechanism in cases of dislocation and subluxation of the patella. In our series of 52 cases with 6-24 months postsurgical evaluation, 46 cases, or 88 percent were rated as good or excellent. It must be emphasized that this technique is used only if the epiphyseal plates are closed.

Evaluation of the Roux-Elmslie-Trillat procedure for knee extensor realignment.

One method for correction of patellofemoral malalignment in acute and recurrent dislocations and subluxations of the patella involves a lateral retinacular release, medial capsular reefing, and medial displacement of the infrapatellar tendon insertion. The procedures was originally described by Roux and later modified and popularized by Elmslie and Trillat. It allows adequate evaluation and easy adjustment of the extensor mechanism at the time of surgery. This current report is an evaluation of 116 of these procedures followed for at least one year and examined by an orthopaedic surgeon. This evaluation indicates that this is a satisfactory method for prevention of recurrent subluxation of the patella with recurrence in only 7% of the cases. A critical evaluation of the results of the procedure reveals only 66% were rated as good or excellent. The results were directly related to associated intraarticular pathology such as hemarthrosis, patellar chondromalacia, degenerative changes on the femoral or tibial articular surfaces, torn or absent semilunar cartilages, torn anterior cruciate ligaments, and insufficient correction of either patella alta or a wide quadriceps angle. The procedure has been slightly modified and the indications for the procedure have been revised.

The fate of the acromioclavicular joint in athletic injuries.

Of 164 acromioclavicular joint injuries to midshipmen at the US Naval Academy between July 1973 and November 1978, 99 were Type 1, 52 were Type 2, and 13 were Type 3. Follow-up examinations revealed that 36% of Type 1, 48% of Type 2, and 69% of Type 3 patients had residual symptoms. Positive physical findings were present in 43% of Type 1, 77% of Type 2, and 100% of Type 3 injuries. Roentgenographic changes were noted in 70% of Type 1, 75% of Type 2, and 100% of Type 3 patients. This evaluation suggests aggressive treatment and rehabilitation are indicated in acute acromioclavicular injuries. Residual problems from Types 1 and 2 injuries are much more frequent than indicated in the literature. Symptoms in Type 1, but not in Type 2, injuries are directly related to the presence of positive physical findings. Roentgenographic changes are extremely common and are not correlated with symptoms. Treatment of Type 2 injuries with the acromioclavicular immobilizer resulted in fewer complications than symptomatic treatment.

Women midshipmen in sports.

This is a study of the physical performance and injury rate for seven classes of women midshipmen at the United States Naval Academy. Women comprise only 6.2% of the brigade of midshipmen, but men and women live in the same dormitory, undergo the same physical training and fitness tests, study the same academic curriculum, and live in an environment where performance and activities can be constantly monitored. The required number of hours of physical education are the same for men and women. The conclusions from this study are: (1) women midshipmen continue to improve their fitness level more rapidly than men; (2) while some disparities in performance are correctly attributed to physiological differences, many of the present disparities should be attributed to societal conditions; (3) should physical performance requirements ever become the same, women will have to work harder than men to achieve the same standards because of the physiological differences; (4) women continue to seek medical attention for stress-related problems (i.e., shin splints, stress fractures) more often than men, but do so less often as they become acclimated to the active life of the Naval Academy; (5) women midshipmen have the same number of serious injuries as men, and in some sports are more susceptible to certain types of injuries.

Women in sports: the Naval Academy experience.

Women were first admitted to the United States Naval Academy with the Class of 1980. The physical performance of 63 women in that class along with 69 in the Class of 1981 and 78 in the Class of 1982 is compared to the performance of a random sample of male midshipmen in the same Classes. The Department of Physical Education made some adjustments in the fitness program for women but did not change the objectives. The number of hours of physical education was the same for the men and women. Performance tests show that the women have scored better than had been anticipated and that the scores have improved with each Class. The women have averaged three times as many visits to the orthopaedic clinic for stress-related injuries than the men, but as the women have become acclimated to a more active life, they have sought medical attention for these problems less often. The women in these three Classes have had no trauma-related orthopaedic surgery. It is anticipated that when women midshipmen begin to participate in the same vigorous sports as men, e.g., soccer, lacrosse, and others, that injuries will increase. We conclude that physical fitness requirements for women will become increasingly similar to the men's requirements. At this time, the performance of women is often a result of society's conditioning rather than apparent physiologic differences between the sexes.

Use of phenylbutazone in sports medicine: understanding the risks.

Despite the widespread use of phenylbutazone, its safety is still a controversial issue. One example of its toxicity is the fact that phenylbutazone has now replaced chloramphenicol as the most common cause of fatal drug-related aplastic anemia. To evaluate the toxicity of phenylbutazone as it is commonly used in sports medicine, a group of 3,000 healthy young athletes was studied following 1-week courses of phenylbutazone for various sports-related inflammatory problems. No serious adverse reactions were encountered. Four percent of the patients experienced mild gastrointestinal disturbances with less than 1% of the patients being forced to discontinue the medication. Compiling the results of other studies, it is estimated that the risk of a serious reaction to phenylbutazone is less than 1 per 100,000 when the drug is used by healthy young individuals for periods of 1 week or less. This risk increases significantly in older patients and with longer periods of treatment. Although phenylbutazone is widely prescribed in sports medicine, there appears to be insufficient information regarding its possible effects on athletic performance. Its capacity to cause significant fluid retention with secondary dilutional anemis, for example, could, in certain instances, have an adverse effect on overall performance if the drug is continued after the athlete returns to competition. Further study in this area is urged.

Patellofemoral problems in runners.

Unlike twisting and cutting sports, in which there are torsional forces placed on the knee, distance running involves straight line motion. The biomechanics of running usually insure a relatively smooth tracking of the patella in the femoral groove, so it is rare for a runner to experience an acute traumatic injury of the joint. Since such injuries are rare, this article concentrates on stress-related patellofemoral syndromes that are seen in runners.

Orthopaedic complications of childhood neurofibromatosis.

Neurofibromatosis is a genetically transmitted, multisystemic disorder characterized by abnormalities of the skin, nervous tissue, and bone. Many of the serious problems associated with this disease are orthopaedic in nature. The treatment and plan of care for a child with neurofibromatosis must be comprehensive and consistent. Nursing care should address the developmental, physical, and emotional needs of the child, as well as the psychologic concerns and educational needs of the child and parents.

Orthopaedic complications of childhood neurofibromatosis.

Neurofibromatosis is a genetically transmitted, multisystemic disorder characterized by abnormalities of the skin, nervous tissue, and bone. Many of the serious problems associated with this disease are orthopaedic in nature. The treatment and plan of care for a child with neurofibromatosis must be comprehensive and consistent. Nursing care should address the developmental, physical, and emotional needs of the child, as well as the psychologic concerns and educational needs of the child and parents.