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Active fault data are commonly used in seismic hazard assessments, but there are challenges in deriving the slip rate, geometry, and frequency of earthquakes along active faults. Herein, we present the open-access geospatial Malawi Seismogenic Source Model (MSSM; https://doi.org/10.5281/zenodo.5599616), which describes the seismogenic properties of faults that formed during ongoing east African rifting in Malawi. We first use empirically derived constraints to geometrically classify active faults into section, fault, and multifault seismogenic sources. For sources in the North Basin of Lake Malawi, slip rates can be derived from the vertical offset of a seismic reflector that dated lake cores indicate is 75 ka. Elsewhere, slip rates are constrained from advancing a systems-based approach that partitions geodetically derived rift extension rates in Malawi between seismogenic sources using a priori constraints on a regional strain distribution and a hanging wall flexural extension in magma-poor continental rifts. Slip rates are then combined with source geometry and empirical scaling relationships to estimate earthquake magnitudes and recurrence intervals, and their uncertainty is described from the variability in logic tree outcomes used in these calculations. Sources in the MSSM are 5–269 km long, which implies that large-magnitude (Mw 7–8) earthquakes may occur in Malawi. However, low slip rates (0.05–2 mm yr−1) mean that the frequency of such events will be low (recurrence intervals of ∼103–104 years). We also find that, for 9 out of 11 faults in Lake Malawi's North Basin, differences in the slip rates, when estimated independently from the geodetic data and the offset seismic reflector, are not statistically significant. The MSSM represents an important resource for investigating Malawi's increasing seismic risk and provides a framework for incorporating active fault data into seismic hazard assessment elsewhere in the East African Rift and other tectonically active regions.

The Lake Malawi (Nyasa) Rift, in the East African Rift System (EARS), is an ideal modern analogue for the study of extensional tectonic systems in low strain rate settings. The seismically active rift contains the 700-m-deep Lake Malawi, one of the world’s oldest and largest freshwater lakes with one of the most diverse endemic faunal assemblages on Earth. Modern and reprocessed legacy multichannel seismic-reflection data are constrained by velocity information from a wide-angle seismic experiment to evaluate variability in extension, segmentation, and timing of fault development along the 550-km-long rift zone. Fault geometries and patterns of synrift sediment fills show that the Lake Malawi Rift is composed of three asymmetric rift segments, with intervening accommodation zone morphologies controlled by the degree of overlap between segment border faults. Most extension occurs on the basin border faults, and broadly distributed extension is only observed at one accommodation zone, where no border fault overlap is observed. Structural restorations indicate a weakly extended rift system (∼7 km), with diminishing values of extension and thinner rift fill from north to south, suggesting a progressively younger rift to the south. There is no evidence of diking, sill injection, or extrusives within the synrift fill of the Lake Malawi Rift, although the volcanic load of the Rungwe magmatic system north of the lake and related subsidence may explain the presence of anomalously thick synrift fill in the northernmost part of the lake. The thickest synrift depocenters (∼5.5 km) are confined to narrow 10- to 20-km-wide zones adjacent to each rift segment border fault, indicating concentration of strain on border faults rather than intrarift faults. Intrarift structures control axial sediment delivery in the North and Central rift segments, focusing sediment into confined areas resulting in localized overpressure and shale diapirs. The asymmetric, basement-controlled relief was established early in rift development. When overprinted with frequent high-amplitude hydroclimate fluctuations, which are well documented for this basin, the resulting highly variable landscape and lake morphometry through time likely impacted the diverse endemic faunas that evolved within the basin. New seismic-reflection data, augmented by wide-angle seismic data and age constraints from drill core, offer the most highly resolved 3D view to date of latest Cenozoic extensional deformation in East Africa and provide a foundation for hazards analysis, resource assessments, and constraining deformation in a low strain rate, magma-poor active rift.

Active fault data are commonly used in seismic hazard assessments, but there are challenges in deriving the slip rate, geometry, and frequency of earthquakes along active faults. Herein, we present the open-access geospatial Malawi Seismogenic Source Database (MSSD), which describes the seismogenic properties of faults that have formed during East African rifting in Malawi. We first use empirical observations to geometrically classify active faults into section, fault, and multi-fault seismogenic sources. For sources in the North Basin of Lake Malawi, slip rates can be derived from the vertical offset of a seismic reflector that is estimated to be 75 ka based on dated core. Elsewhere, slip rates are constrained from advancing a ‘systems-based’ approach that partitions geodetically-derived rift extension rates in Malawi between seismogenic sources using a priori constraints on regional strain distribution in magma-poor continental rifts. Slip rates are then combined with source geometry and empirical scaling relationships to estimate earthquake magnitudes and recurrence intervals, and their uncertainty is described from the variability of outcomes from a logic tree used in these calculations. We find that for sources in the Lake Malawi’s North Basin, where slip rates can be derived from both the geodetic data and the offset seismic reflector, the slip rate estimates are within error of each other, although those from the offset reflector are higher. Sources in the MSSD are 5–200 km long, which implies that large magnitude (MW 7–8) earthquakes may occur in Malawi. Low slip rates (0.05–2 mm/yr), however, mean that the frequency of such events will be low (recurrence intervals ~103–104 years). The MSSD represents an important resource for investigating Malawi’s increasing seismic risks and provides a framework for incorporating active fault data into seismic hazard assessment in other tectonically active regions.

Magmatism is often invoked as critical for assisting strain focusing during continental rift development, and in driving lithospheric thinning and continental rupture. Accordingly, models of rift basin evolution in the East African Rift System (EARS) have previously focused on magma-rich basins; however, a complete understanding of how magmatism drives rift evolution requires analyses of both magma-rich and magma-poor extensional environments. We investigate a ∼10-million-year history of fault development in the magma-poor Lake Tanganyika Rift of the Western branch of the EARS, utilizing reprocessed legacy and high-resolution commercial seismic reflection datasets. Unlike the magma-rich Eastern branch, fault-strain does not focus into the basin floor along the rift axis within the first ∼10 million years of rift development. Instead, large rift-bounding faults (border faults) accommodate the majority of extensional strain (∼90% of an estimated 11.5 km of extension over the 52 km-wide rift) from rift inception through to present-day rifting. The Western branch of the EARS is also characterized by crustal structure and fault geometries that differ from those observed for successfully rifted magma-poor margins (e.g., listric normal faulting with mid-crustal detachments). In the absence of voluminous magmatism, we suggest that either (1) complete continental rupture cannot be achieved in the Western branch of the EARS, or (2) continental break up in the Western branch will proceed under a model that contrasts with that invoked for both the Eastern branch and magma-poor rifted margins generally.

Against a background of growing concern over whether the National Curriculum for Physical Education (NCPE) in England is being delivered effectively in primary schools, this paper examines philosophically those intrinsic values which lie at the heart of physical education and should be preserved. The distinction between intrinsic and extrinsic values is explained and it is argued that the primacy of intrinsic values needs to be taken into account when considering the primary NCPE. Three distinct sources of intrinsic of value are identified: an obligation to truth; moral values; and the desire for happiness. It is argued all three sources of value can be found in physical education but the last one, the desire for happiness, is the most important. The view is defended that this source of value should be particularly prominent in the primary NCPE and its delivery. In particular, it is important at key stage one that values which are realised through play are maintained. It is concluded these values are best...

Rifamides are important components in the treatment of tuberculosis. However, it is well documented that these drugs can have immunosuppressive activity, a property of these drugs that is particularly relevant to AIDS patients. In this study, we have shown that a number of rifamide analogues have the potential to block tumour necrosis factor (TNF)- or phorbol myristate acetate-induced NF-kappaB activation. As TNF is important in the host defence against tuberculosis, suppression of this activity may provide a potential mechanism of rifamide immunosuppressive activity.

Background: Good compliance with antibiotic therapy is critical for successful management of sexually transmitted diseases (STDs). Goal of This Study: To evaluate the use of user-friendly drug packaging as a means of improving patient compliance with STD therapy and the acceptability of the packaging. Study Design: Compliance of patients with STDs with treatment regimens for three different STD syndromes, using antibiotics packed in standard medicine packaging (SP), was compared to that of patients using calendar blister packaged drugs. Compliance was measured by counting the remaining pills at two return visits. Questionnaires were used to evaluate acceptability of the packs. Results: Compliance was significantly better among patients using the calendar blister packs than among those using standard packs, irrespective of dosing frequency. The degree of poor compliance increased with increasing dosing frequency. There was a high level of satisfaction with the blister pack among patients and health care workers. Conclusion: Compliance can be improved by the introduction of user-friendly drug packaging, especially for more complex dosing regimens.

Buruli ulcer is a chronic and progressive necrotizing ulcer for which there is no medical treatment. Historically, a soluble toxin (factor) derived from the causative Mycobacterium ulcerans was found to induce the massive necrosis of skin and s.c. tissue seen in this condition. However, the persistence of the disease is thought to be caused by a lack of any immune response. We therefore investigated whether the factor was related to immunosuppression. A protocol to partially purify the factor was developed, and its effects on immune competent cells were tested. The factor produced >95% inhibition of LPS-induced release of TNF and IL-10 from human monocytes and caused a loss of adherence of these cells without cell death. The factor also blocked the production of IL-2 from activated T lymphocytes. The factor had no effect on TNF-induced cytotoxicity, but abrogated TNF-induced NF-κB activation. Surprisingly, a synergy was observed between the factor and phorbol ester-directed NF-κB activation. The factor had no effect on IL-1- or LPS-induced NF-κB activity, indicating selective activity of the factor. The factor did not inhibit the degradation of IκBα induced by TNF, indicating that the target for its activity lies within an undefined part of the TNF signaling mechanism. The data indicate that the localized immunosuppression associated with Buruli ulcer relates to the activity of the released factor, and this may provide a target for future therapeutic strategies for this intractable disease.

The benzylborato-azasilazirconacyclobutane complex 1 was formed by ligand cyclometalation upon reaction of {l_brace}(Me{sub 3}Si){sub 2}N{r_brace}{sub 2}Zr(CH{sub 2}Ph){sub 2} with B(C{sub 6}F{sub 5}){sub 3}. Quantitative analysis of the {sup 1}H NOESY time course of 1 using the conformer population analysis method demonstrates that the dominant conformers in solution are rapidly exchanging benzyl borate rotamers, closely bound to the asymmetric zirconium. The ring rotates such that the benzylic methylene eclipses the metallocyclobutylmethylene in the majority of the population and the free amide nitrogen in the minority of the population. A molecular dynamics approach was required to solve this solution structure because a mixture of static conformations does not satisfactorily explain the observed spectra.

An apparent increase in the incidence of S. Brandenburg in New Zealand, coupled with the possibility that the virulence of the organism may also be changing, prompted this study.Three typing methods: macro-restriction fragment length polymorphism (MRFLP) profiling using pulsed field gel electrophoresis (PFGE), plasmid profiling and antimicrobial susceptibility profiling were used to determine strain diversity amongst 115 recent and historical isolates of S. Brandenburg from both human cases and non-human sources.Antimicrobial resistance was noted only in three isolates. Plasmids of varying sizes were found in 31 isolates. MRFLP analysis resulted in 13 different patterns. Combining the three sets of typing data yielded 24 composite types. Comparison of composite type, isolation date and geographical location of case allowed the retrospective recognition of seven potential clusters during the 5-year study period. Composite types of 24 (80%) of the non-human isolates tested were indistinguishable from human isolates, suggesting that human infection may be via a number of vehicles.Although not cost-effective for routine use on all salmonella isolates, the methods used in this study are an important adjunct to serotyping for discrimination within an emerging serotype.

Trametinib is an orally bioavailable mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor with antineoplastic activity. The compound specifically binds to MEK1 and MEK2, resulting in inhibition of growth factor-mediated cell signalling and cellular proliferation in various cancers. Originally developed by Japan Tobacco, GlaxoSmithKline has licensed exclusive worldwide rights to the compound and conducted development in a number of different cancer types. Trametinib, as a monotherapy, has been approved in the US for the treatment of unresectable or metastatic malignant melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. The compound, as a monotherapy, has also been submitted for regulatory review in the EU for BRAF mutation-positive malignant melanoma, and is in phase III development in Europe, Argentina, Canada and Oceania. Phase II development is underway for pancreatic cancer, non-small cell lung cancer and relapsed or refractory leukaemias. GlaxoSmithKline is also developing trametinib for use in combination with dabrafenib in BRAF V600 mutation-positive metastatic cutaneous melanoma; the combination is at the preregistration stage in the EU and a phase III clinical programme is underway worldwide. Phase II development for this combination is also underway in colorectal cancer. Several phase I trials have also been initiated to evaluate trametinib in combination with other drugs for the treatment of various solid tumours and haematological malignancies. A paediatric oral solution formulation has been assessed against the oral tablet formulation in a phase I trial. This article summarizes the milestones in the development of trametinib leading to this first approval for unresectable or metastatic BRAF mutation-positive malignant melanoma.

The efficacy and safety of optimally titrated once-daily (CD) and twice-daily (SR) diltiazem were compared in 111 patients with mild to moderate systemic hypertension [seated diastolic blood pressure (DBP) > or = 95 mmHg and < or = 114 mmHg] in a multicenter, randomized, double-blind, placebo run-in, parallel-group trial. Following a 4 week washout and placebo-controlled run-in period, patients were randomized to receive diltiazem CD 180 mg and matching placebo (n = 54), or diltiazem SR 90 mg bid (n = 57). Total daily doses were titrated from 180 mg to 360 mg to achieve a goal of seated DBP < 90 mmHg during a 6 week titration period. The patients continued to receive their optimal dose for a 6 week follow-up period. Ninety-six (96) patients (diltiazem CD: 47, diltiazem SR: 49) completed the study protocol, with 60% of the diltiazem CD and 55% of the diltiazem SR patients achieving the goal of seated DBP of < 90 mmHg (p = 0.685). Although significant decreases occurred in seated and standing measurements of diastolic and systolic BP and heart rate with treatment in both groups, there were no significant differences between treatment groups. Both medications were well tolerated, with a similar frequency of adverse effects [diltiazem CD: 24/54 (37%) patients; diltiazem SR: 24/57 (42.1%) patients] with the most frequently reported adverse effects being headache and edema.

AIMS--To compare the predictive value of immunoblotting and enzyme linked immunosorbent assay (ELISA) in diagnosing Lyme borreliosis. METHODS--An ELISA using a whole cell sonicate of the B31 strain of Borrelia burgdorferi was used to screen samples submitted for Lyme borreliosis serology. A total of 1222 serum samples reactive in the ELISA were tested by immunoblotting also using the B31 strain. Patients with other spirochaetal diseases were tested by both methods to assess specificity, while those with erythema migrans were used to evaluate sensitivity. Subjects with different clinical conditions, which may have been associated with Lyme borreliosis, were tested using both techniques. RESULTS--Only 16.3% of serum samples from patients submitted for Lyme borreliosis serology which were reactive by ELISA were confirmed as positive by immunoblotting. This is unlikely to represent a sensitivity problem as 51% of samples from 53 patients with erythema migrans were detected by immunoblotting compared with only 28% by ELISA. Patients whose samples were negative by ELISA were also negative by immunoblotting. Serum samples from patients with relapsing fever were reactive in both ELISA and by immunoblotting, but for other test groups immunoblotting offered increased specificity. CONCLUSIONS--Not all ELISA results could be confirmed by immunoblotting. Yet immunoblotting was both more sensitive and specific than ELISA techniques. As a result of these observations all ELISA results should be serologically confirmed by immunoblotting. Though immunoblotting is not suited to large scale screening of samples, it can be used satisfactorily in conjunction with ELISA methods to improve the predictive value of serological tests for Lyme borreliosis.

Sensitization to cockroach allergen is one of the strongest predictors of asthma morbidity, especially among African Americans.Our aims were to determine the genomic basis of cockroach sensitization and the specific response to cockroach antigen.We investigated the Th1/Th2 cytokine profile of co-cultured plasmacytoid dendritic cells (pDCs) and CD4+ T cells and the 'transcript signature' of the immune response to cockroach antigen using high-throughput expression profiling of co-cultured cells.We observed significantly elevated levels of IL-13, IL-10, and TNF-alpha, but undetectable levels of IL-12p70 and IFN-alpha, when cultures were exposed to crude cockroach antigen. A significant difference was observed for IL-13 between cockroach-allergic and non-allergic individuals (P=0.039). Microarray analyses demonstrated a greater response at 48 h compared with 4 h, with 50 genes being uniquely expressed in cockroach antigen-treated cells, including CD14, S100A8, CCL8, and IFI44L. The increased CD14 expression was further observed in purified pDCs, human monocytic THP-1 cells, and the supernatant of co-cultured pDCs and CD4+ T cells on exposure to cockroach extract. Furthermore, the most differential expression of CD14 between cockroach allergy and non-cockroach allergy was only observed among individuals with the CC 'high-risk' genotype of the CD14-260C/T. Ingenuity Pathways Analysis analyses suggested the IFN signalling as the most significant canonical pathway.Our results suggest that these differentially expressed genes, particularly CD14, and genes in the IFN signalling pathway may be important candidates for further investigation of their role in the immune response to cockroach allergen.

Improved measurement of the plasma concentration of nitrendipine demonstrated a plasma half-life of 17-21 h, allowing once-daily (o.d.) instead of currently twice-daily (b.i.d.) dosing. To determine the effectiveness of nitrendipine given o.d. vs. b.i.d., 78 hypertensive patients, [supine diastolic blood pressure (DBP) of 95-114 mm Hg] were randomized in a double-blind fashion to 12 weeks of treatment with either nitrendipine 10 mg b.i.d. (n = 39) or nitrendipine 20 mg o.d. (n = 39) after a 2-week placebo baseline period. Blood pressures (BPs) were measured in the morning at the end of the dosing interval. Mean +/- SD reduction in supine systolic BP (SBP) and DBP in patients evaluable for efficacy (greater than or equal to 14 days treatment) were 7.2 +/- 16.5 and 7.7 +/- 10.3 mm Hg, respectively, after nitrendipine b.i.d. (n = 38) and 9.4 +/- 15.1 and 9.5 +/- 7.0 mm Hg, respectively, after nitrendipine o.d. (n = 36). Similar falls in BP were found for both regimens in patients completing the full 12 weeks of treatment period (n: o.d. = 28, b.i.d. = 32). Discontinuation due to adverse experiences (AEs) occurred in three patients on b.i.d. and eight patients on o.d., the latter mostly in the first 2 weeks of therapy. Overall, AEs were higher in the o.d. group (% AEs at least possibly related to study medication: o.d. = 44%, b.i.d. = 33%). Most frequent AEs were headache and flushing.(ABSTRACT TRUNCATED AT 250 WORDS)

Sjögren's syndrome (SS) and sarcoidosis are diseases that can affect the salivary glands and result in the loss of salivary gland function. Most of the criteria used for the diagnosis of SS exclude sarcoidosis before establishing the diagnosis of SS. However, several reports have suggested the coexistence of both SS and sarcoidosis in the same patient.The purpose of this study was to present five cases that support a true coexistence of sarcoidosis and SS.Clinical and laboratory findings of patients with evidence of having both SS and sarcoidosis were reviewed. The diagnosis of SS was based on the European community criteria; the diagnosis of sarcoidosis was based on the presence of serological, radiographic and/or histopathologic findings that are consistent with sarcoidosis.All patients fulfilled the criteria for the diagnosis of both diseases.Our findings appear to support a true coexistence of sarcoidosis with SS. Therefore, it is reasonable to suggest removing the exclusion of sarcoidosis from the diagnostic criteria for SS.

To examine the effect of trimester specific and pregnancy average total trihalomethane (TTHM) exposure on infant birth weight, low birth weight, and intrauterine growth retardation in term births, as well as gestational age and preterm delivery in all births.Cross sectional analysis of 56 513 singleton infants born to residents of Massachusetts during 1990. City specific aggregate data were used to estimate maternal exposure to TTHM concentration; individual maternal information was used to adjust for confounding.Increased pregnancy average and second trimester TTHM exposure were associated with small for gestational age and reductions in birth weight after adjusting for potential confounding variables. Compared to/=60 micro g/l, pregnancy average TTHM exposure over 80 micro g/l was associated with a 32 g reduction in birth weight. There was a 23 g reduction in birth weight in infants born to mothers exposed to greater than 80 micro g/l TTHM during the second trimester. For each 20 micro g/l increase in TTHM, the estimated reduction in birth was 2.8 g for pregnancy average exposure and 2.6 g for second trimester exposure. An increased risk of small for gestational age births was found for pregnancy average (odds ratio (OR) 1.14; 95% CI 1.02 to 1.26) and second trimester (OR 1.13, 95% CI 1.03 to 1.24) TTHM levels greater than 80 micro g/l. There was no evidence of an association between preterm delivery and increased TTHM levels, but there were slight increases in gestational duration associated with TTHM concentrations.Maternal exposure to THMs may be associated with fetal growth retardation. Our findings are consistent with most previous work, although we generally found smaller effects of TTHMs on low birth weight and intrauterine growth retardation.

In higher eukaryotes, the 5S ribosomal DNA (5S rDNA) is organized in tandem arrays with repeat units composed of a coding region and a non-transcribed spacer sequence (NTS). These tandem arrays can be found on either one or more chromosome pairs. 5S rDNA copies from the tilapia fish, Oreochromis niloticus, were cloned and the nucleotide sequences of the coding region and of the non-transcribed spacer were determined. Moreover, the genomic organization of the 5S rDNA tandem repeats was investigated by fluorescence IN SITU hybridization (FISH) and Southern blot hybridization. Two 5S rDNA classes, one consisting of 1.4-kb repeats and another one with 0.5-kb repeats were identified and designated 5S rDNA type I and type II, respectively. An inverted 5S rRNA gene and a 5S rRNA putative pseudogene were also identified inside the tandem repeats of 5S rDNA type I. FISH permitted the visualization of the 5S rRNA genes at three chromosome loci, one of them consisting of arrays of the 5S rDNA type I, and the two others corresponding to arrays of the 5S rDNA type II. The two classes of the 5S rDNA, the presence of pseudogenes, and the inverted genes observed in the O. niloticus genome might be a consequence of the intense dynamics of the evolution of these tandem repeat elements.

There are few reports on the genomic organization of 5S rDNA in fish species. To characterize the 5S rDNA nucleotide sequence and chromosomal localization in the Neotropical fishes of the genus Brycon, 5S rDNA copies from seven species were generated by PCR. The nucleotide sequences of the coding region (5S rRNA gene) and the nontranscribed spacer (NTS) were determined, revealing that the 5S rRNA genes were highly conserved, while the NTSs were widely variable among the species analyzed. Moreover, two classes of NTS were detected in each species, characterized by base substitutions and insertions-deletions. Using fluorescence in situ hybridization (FISH), two 5S rDNA chromosome loci that could be related to the two 5S rDNA NTS classes were observed in at least one of the species studied. 5S rDNA sequencing and chromosomal localization permitted the characterization of Brycon spp. and suggest a higher similarity among some of them. The data obtained indicate that the 5S rDNA can be an useful genetic marker for species identification and evolutionary studies.

Patellar height and patellar ligament length were assessed pre- and postoperatively in 28 patients who underwent a medial opening wedge proximal tibial osteotomy for varus gonarthrosis. This procedure produced no significant change in patellar ligament length. Pre- and postoperative Insall-Salvati ratios were 0.96+/-0.12 and 0.97+/-0.15, respectively (P=.30). The Insall-Salvati ratio decreased in 29% of patients, and no patient experienced a decline0.07. The distance between the patella and tibiofemoral joint line ("patellar height") decreased in 100% of patients. The mean Blackburne-Peel ratio declined from 0.75+/-0.13 to 0.53+/-0.15 (P.001). Sixty-four percent of the postoperative Blackburne-Peel values satisfied the radiographic criterion for patella infera (Blackburne-Peel ratio0.54). Whereas the loss of patellar height, historically associated with lateral closing wedge proximal tibial osteotomy, is a function of patellar ligament contracture, the decreased distance between the patella and the tibiofemoral joint line following medial opening wedge proximal tibial osteotomy is a function of joint line elevation. The high incidence of patella infera following medial opening wedge proximal tibial osteotomy may have deleterious effects on patellofemoral biomechanics or may complicate subsequent total knee arthroplasty.

The purpose of this study was to examine the reproducibility of biopsy grades at various tissue depths in Sjögren's syndrome. The biopsy grades of 38 minor salivary gland biopsies were examined at 6 microm, 50 microm, 100 microm, 150 microm, 200 microm, and 250 microm tissue depths. Tissue sections were stained with routine hematoxylin and eosin, graded I-IV, and compared with the initial "baseline" biopsy grade. The majority of the biopsies showed a wide range of grade variability at all depths. No tissue depth was consistently reproducible for any grade (Por =0.41, 0.64, 0.91, and 0.20, respectively). The difference between baseline grades and grades of deeper sections was sufficient to impact the diagnosis of Sjögren's syndrome in approximately 60% of the biopsies (P0.001). The overall result of this study suggests that examination of multiple sections of minor salivary gland biopsies is advisable to improve the reliability of the grade when evaluating Sjögren's syndrome.

Oral pemphigoid, defined as cicatricial pemphigoid limited to the oral cavity, is a clinical subset of cicatricial pemphigoid. Like cicatricial pemphigoid, it occurs mostly in middle-aged women and it is uncommon in children under 20 years of age. There are 11 cases of childhood cicatricial pemphigoid published previously in the English language literature, and four of them are oral pemphigoid patients. We present a case of the youngest oral pemphigoid patient reported yet. Because of the rareness of cicatricial pemphigoid in children, delayed diagnosis and treatment have been shown in many cases reported earlier. Clinical awareness and early recognition are, therefore, emphasized.

Many textbooks and articles are available to assist dentists in examining patients, establishing diagnoses for oral lesions and understanding the techniques of biopsy. There is little guidance in the literature, however, on when and how to follow up lesions that have a low index of clinical suspicion, or for which the pathological diagnosis does not demonstrate any overt signs of malignancy or premalignancy.The authors reviewed the literature, talked to numerous clinicians and sought legal opinions regarding how a reasonable and prudent dentist should manage patients with clinically evident oral lesions that do not suggest any adverse long-term effects on the health and safety of the patient.The few guidelines available in the literature, coupled with the observations of the authors and others, allow logical and reasonable interim recommendations to be proposed regarding the frequency of examinations, the timing of invasive procedures and medicolegally prudent documentation guidelines. Future studies are needed to refine these recommendations.Some dentists have been sued for alleged failure to monitor patients, document cases or refer patients with oral lesions. The recommendations provided here can help dentists manage these patients, but they should not be construed as being rigid guidelines or legal standards that apply to all clinical situations. In some cases, the judgment and experience of clinicians may indicate the need to deviate from these recommendations. Refinements of these guidelines may emerge on the basis of future studies.

Posterior shoulder instability is an uncommon clinical entity. It is even more rare in the pediatric population. We report the case of a 10-year-old boy who experienced recurrent posttraumatic posterior shoulder instability that eventually required surgical intervention. A review of the literature revealed no previous report of surgical management of nonobstetrical posttraumatic posterior glenohumeral instability in a skeletally immature individual.

We demonstrate that the homozygous weaver granule neurons cultured on a laminin substratum fail to express inwardly rectifying potassium currents, including a functional G-protein coupled inwardly rectifying potassium (GIRK)2 potassium channel. By contrast, both normal and weaver Purkinje cells express inwardly rectifying potassium currents, and normal granule cells exhibit inwardly rectifying potassium currents inducible with GTP-gamma-S. In protein extracts of the vermal postnatal day (P)5-9 weaver cerebellum, the GIRK2 protein could not be detected by Western analysis, although the GIRK2 protein was detectable in extracts of the normal vermis. Northern analysis indicated that during early postnatal cerebellar development, the GIRK2 mRNA is expressed at extremely low levels being detectable at P18-23 in the normal but not yet in the homozygous weaver cerebellum. Using reverse transcriptase-polymerase chain reaction (RT-PCR), the GIRK2 mRNA was detected in both normal and weaver cerebella, but quantitative PCR confirmed that the weaver cerebellum expressed the GIRK2 gene at significantly lower levels as compared to the normal cerebellum (P = 0.01, paired t-test). Sequencing indicated that the weaver GIRK2 channel gene had the point mutation proposed to be responsible for the weaver phenotype. Rescue of both survival and neurite outgrowth of the cultured vermal weaver granule neurons by verapamil (Liesi and Wright, 1996; Liesi et al., 1999) induced expression of immunocytochemically detectable levels of the GIRK2 protein. Sequencing revealed that the GIRK2 mRNA of the rescued weaver granule neurons remained the mutated variant of the GIRK2 channel gene. Our results indicate that expression of the mutated GIRK2 protein and/or mRNA in the weaver granule neurons may be an indicator of rescue rather than death of the weaver granule neurons. That the weaver granule neurons expressed no functional GIRK2 receptors during a time period of neuronal death and migration failure suggests that the point mutation in the H5 membrane spanning region of the GIRK2 gene may associate with, but not be responsible for the weaver phenotype.

Isoniazid (INH), a widely used drug in the prophylaxis and treatment of tuberculosis, is associated with a 1 to 2% risk of severe and potentially fatal hepatotoxicity. There is evidence that the INH metabolite hydrazine plays an important role in the mechanism of this toxicity. Metabolism of INH leads to the production of hydrazine via both direct and indirect pathways. In both cases, the activity of an INH amidase is required to hydrolyze an amide bond. In the present study, using a model of INH-induced hepatotoxicity in rabbits, pretreatment of rabbits with the amidase inhibitor bis-p-nitrophenyl phosphate 30 min before injection of INH inhibited the formation of INH-derived hydrazine and decreased measures of hepatocellular damage, hepatic triglyceride accumulation, and hypertriglyceridemia. Bis-p-nitrophenyl phosphate also potently inhibited the production of hydrazine from INH in in vitro microsomal incubations (IC50 2 microM). Although hepatic glutathione stores are decreased, they are not depleted in animals with INH-induced hepatotoxicity. Significant effects on hepatic microsomal cytochrome P-450 1A1/2 and cytochrome P-450 2E1 activities suggest that these isozymes may be involved in the mechanism of the toxicity. In conclusion, this study demonstrates the importance of amidase activity in this rabbit model of hepatotoxicity and provides additional evidence in support of the role of hydrazine in the mechanism of INH-induced hepatotoxicity.

Biochemical, immunocytochemical, and molecular biological techniques were used to investigate the expression of N-methyl-D-aspartate (NMDA) receptor subunits in migration-deficient weaver mouse cerebellum in vivo and in primary cultures of the vermal weaver granule neurons with or without a rescue by verapamil. We found that both NMDAR1(zeta1) message and protein were expressed by the weaver granule neurons in situ. Immunocytochemical and biochemical analyses indicated that granule neurons of the weaver cerebellum expressed R1(zeta1) and R2A(epsilon1) subunits but showed little expression of the R2B(epsilon2) subunit. In weaver cerebellum, the R2B(epsilon2) subunit was primarily expressed in nerve fibers of the internal granule cell layer and white matter. Reverse-transcriptase-polymerase chain reaction followed by sequence analysis of the R1(zeta1) subunit indicated that the zeta1 subunit amplicons of both normal and weaver cerebella were identical, and that splice variants with exon 22 (1-2) and with or without exon 5 (a/b) or exon 21 (1-4) were detectable. The R2A(epsilon1), and R2B(epsilon2) subunits of the normal and weaver mouse cerebellum revealed no primary structural differences between the normal and weaver NMDA receptor subunits or the cloned mouse NMDA receptor subunits. In vermal cultures, normal granule neurons expressed all three NMDA receptor subunits (zeta1, epsilon1, and epsilon2), whereas the weaver neurons failed to express the epsilon2 subunit. Rescue of the weaver neurons by verapamil induced expression of the epsilon2 protein along the granule neuronal surfaces. The present results suggest that lack of the epsilon2 subunit in the weaver cerebellum may relate to the lack of functional NMDA receptors and/or to the migratory failure of the weaver granule neurons. Our data further suggest that NMDA receptor-mediated neurotoxicity is an unlikely mediator of neuronal death of the weaver granule neurons. In fact, down-regulation of the NMDA receptor expression and function may be a protective measure of the weaver granule neurons to reduce calcium entry via these receptors.

Summary The effect of sublingual captopril on the pressor response to intubation was studied in 40 patients. Captopril was used in one of two doses (12.5 mg and 25 mg) 25 minutes before tracheal intubation. Both doses were associated with a significant reduction in the pressor response to intubation (p < 0.05) compared to placebo, but no significant difference existed between the two doses. Neither dose controlled changes in heart rate at intubation. Untoward hypotension occurred in the treatment groups. Caution is advised in the peri-operative use of angiotensin-converting enzyme inhibitors.