Laparoscopic management of gall bladder perforation secondary to typhoid-induced acalculous cholecystitis: A rare entity.

Gall bladder perforation as a sequel of typhoid-induced acalculous cholecystitis is a rare clinical encounter, reported sparsely in literature. Here, we discuss a case wherein successful laparoscopic management of typhoid-induced gall bladder perforation was performed. A 24-year-old female presented with a history of 5 days of fever and acute pain in the abdomen for 2 days. Computed tomography scan suggested gall bladder perforation which was confirmed on diagnostic laparoscopy. Laparoscopic cholecystectomy with peritoneal lavage was performed. The patient did well postoperatively and was discharged on post-operative day 4 after drain removal. One should be aware about the possibility of gall bladder perforation as a sequel of acalculous cholecystitis in typhoid fever. Minimal access surgery techniques can be applied for confirming the diagnosis as well as the definitive treatment.

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity.

The literature review presented here details recent research involving members of the poly(ADP-ribose) polymerase (PARP) family of proteins. Among the 17 recognized members of the family, the human enzyme PARP1 is the most extensively studied, resulting in a number of known biological and metabolic roles. This review is focused on the roles played by PARP enzymes in host-pathogen interactions and in diseases with an associated inflammatory response. In mammalian cells, several PARPs have specific roles in the antiviral response; this is perhaps best illustrated by PARP13, also termed the zinc finger antiviral protein (ZAP). Plant stress responses and immunity are also regulated by poly(ADP-ribosyl)ation. PARPs promote inflammatory responses by stimulating proinflammatory signal transduction pathways that lead to the expression of cytokines and cell adhesion molecules. Hence, PARP inhibitors show promise in the treatment of inflammatory disorders and conditions with an inflammatory component, such as diabetes, arthritis, and stroke. These functions are correlated with the biophysical characteristics of PARP family enzymes. This work is important in providing a comprehensive understanding of the molecular basis of pathogenesis and host responses, as well as in the identification of inhibitors. This is important because the identification of inhibitors has been shown to be effective in arresting the progression of disease.

Computational and Experimental Studies of ADP-Ribosylation.

The macrodomains are a multifunctional protein family that function as receptors and enzymes acting on poly(ADP-ribose), ADP-ribosylated proteins, and other metabolites of nicotinamide adenine dinucleotide (NAD+). Several new functions for macrodomains, such as nucleic acid binding and protein-protein interaction, have recently been identified in this family. Here, we discuss methods for the identification of new macrodomains in viruses and the prediction of their function. This is followed by the expression and purification of these proteins following overexpression in bacterial cells and confirmation of folding and function using biophysical methods.

Structural studies of E73 from a hyperthermophilic archaeal virus identify the "RH3" domain, an elaborated ribbon-helix-helix motif involved in DNA recognition.

Hyperthermophilic archaeal viruses, including Sulfolobus spindle-shaped viruses (SSVs) such as SSV-1 and SSV-Ragged Hills, exhibit remarkable morphology and genetic diversity. However, they remain poorly understood, in part because their genomes exhibit limited or unrecognizable sequence similarity to genes with known function. Here we report structural and functional studies of E73, a 73-residue homodimeric protein encoded within the SSV-Ragged Hills genome. Despite lacking significant sequence similarity, the nuclear magnetic resonance (NMR) structure reveals clear similarity to ribbon-helix-helix (RHH) domains present in numerous proteins involved in transcriptional regulation. In vitro double-stranded DNA (dsDNA) binding experiments confirm the ability of E73 to bind dsDNA in a nonspecific manner with micromolar affinity, and characterization of the K11E variant confirms the location of the predicted DNA binding surface. E73 is distinct, however, from known RHH domains. The RHH motif is elaborated upon by the insertion of a third helix that is tightly integrated into the structural domain, giving rise to the "RH3" fold. Within the homodimer, this helix results in the formation of a conserved, symmetric cleft distal to the DNA binding surface, where it may mediate protein-protein interactions or contribute to the high thermal stability of E73. Analysis of backbone amide dynamics by NMR provides evidence of a rigid core, fast picosecond to nanosecond time scale NH bond vector motions for residues located within the antiparallel ß-sheet region of the proposed DNA-binding surface, and slower microsecond to millisecond time scale motions for residues in the α1-α2 loop. The roles of E73 and its SSV homologues in the viral life cycle are discussed.

Improving prompt effectiveness in diabetes care: an intervention study.

Electronic medical records (EMRs) should support clinical decision making to further quality care delivery. This study describes 1 academic medical group's efforts to leverage their EMR's decision-support functionality to improve quality care delivery. A nested, time-series, quasiexperimental design compared 3 different implementation strategies for EMR prompting at 5 primary care clinics in a single academic medical group. The primary outcome was the ordering of all indicated diabetes monitoring tests before the end of the visit. The authors analyzed 16 511 visits performed on 3730 patients. The rate of ordering all indicated tests at the time of the visit increased from 29% with no prompts to 49% (P < .001) with appropriately designed prompts and training support. EMR-generated prompts may be more likely to increase ordering of recommended monitoring tests when clinic workflow, staff training, and medical culture are incorporated into the prompt delivery.

An approach to improve LOINC mapping through augmentation of local test names.

Mapping medical test names into a standardized vocabulary is a prerequisite to sharing test-related data between health care entities. One major barrier in this process is the inability to describe tests in sufficient detail to assign the appropriate name in Logical Observation Identifiers, Names, and Codes (LOINC®). Approaches to address mapping of test names with incomplete information have not been well described. We developed a process of "enhancing" local test names by incorporating information required for LOINC mapping into the test names themselves. When using the Regenstrief LOINC Mapping Assistant (RELMA) we found that 73/198 (37%) of "enhanced" test names were successfully mapped to LOINC, compared to 41/191 (21%) of original names (p=0.001). Our approach led to a significantly higher proportion of test names with successful mapping to LOINC, but further efforts are required to achieve more satisfactory results.

Internal dynamics of the tryptophan repressor (TrpR) and two functionally distinct TrpR variants, L75F-TrpR and A77V-TrpR, in their l-Trp-bound forms.

Backbone amide dynamics of the Escherichia coli tryptophan repressor protein (WT-TrpR) and two functionally distinct variants, L75F-TrpR and A77V-TrpR, in their holo (l-tryptophan corepressor-bound) form have been characterized using (15)N nuclear magnetic resonance (NMR) relaxation. The three proteins possess very similar structures, ruling out major conformational differences as the source of their functional differences, and suggest that changes in protein flexibility are at the origin of their distinct functional properties. Comparison of site specific (15)N-T(1), (15)N-T(2), (15)N-{(1)H} nuclear Overhauser effect, reduced spectral density, and generalized order (S(2)) parameters indicates that backbone dynamics in the three holo-repressors are overall very similar with a few notable and significant exceptions for backbone atoms residing within the proteins' DNA-binding domain. We find that flexibility is highly restricted for amides in core α-helices (i.e., helices A-C and F), and a comparable "stiffening" is observed for residues in the DNA recognition helix (helix E) of the helix D-turn-helix E (HTH) DNA-binding domain of the three holo-repressors. Unexpectedly, amides located in helix D and in adjacent turn regions remain flexible. These data support the concept that residual flexibility in TrpR is essential for repressor function, DNA binding, and molecular recognition of target operators. Comparison of the (15)N NMR relaxation parameters of the holo-TrpRs with those of the apo-TrpRs indicates that the single-point amino acid substitutions, L75F and A77V, perturb the flexibility of backbone amides of TrpR in very different ways and are most pronounced in the apo forms of the three repressors. Finally, we present these findings in the context of other DNA-binding proteins and the role of protein flexibility in molecular recognition.

Backbone amide dynamics studies of Apo-L75F-TrpR, a temperature-sensitive mutant of the tryptophan repressor protein (TrpR): comparison with the (15)N NMR relaxation profiles of wild-type and A77V mutant Apo-TrpR repressors.

Backbone amide dynamics studies were conducted on a temperature-sensitive mutant (L75F-TrpR) of the tryptophan repressor protein (TrpR) of Escherichia coli in its apo (i.e., no l-tryptophan corepressor-bound) form. The (15)N NMR relaxation profiles of apo-L75F-TrpR were analyzed and compared to those of wild-type (WT) and super-repressor mutant (A77V) TrpR proteins, also in their apo forms. The (15)N NMR relaxation data ((15)N-T(1), (15)N-T(2), and heteronuclear (15)N-{(1)H}-nOe) recorded on all three aporepressors at a magnetic field strength of 600 MHz ((1)H Larmor frequency) were analyzed to extract dynamics parameters, including diffusion tensor ratios (D(∥)/D(⊥)), correlation times (τ(m)) for overall reorientations of the proteins in solution, reduced spectral density terms [J(eff)(0), J(0.87ω(H)), J(ω(N))], and generalized order parameters (S(2)), which report on protein internal motions on the picosecond to nanosecond and slower microsecond to millisecond chemical exchange time scales. Our results indicate that all three aporepressors exhibit comparable D(∥)/D(⊥) ratios and characteristic time constants, τ(m), for overall global reorientation, indicating that in solution, all three apoproteins display very similar overall shape, structure, and rotational diffusion properties. Comparison of (15)N NMR relaxation data, reduced spectral density profiles, and generalized S(2) order parameters indicated that these parameters are quite uniform for backbone amides positioned within the four (A-C and F) core α-helices of all three aporepressors. In contrast, small but noticeable differences in internal dynamics were observed for backbone amides located within the helix D-turn-helix E DNA-binding domain of the apo-TrpR proteins. The significance of these dynamics differences in terms of the biophysical characteristics and ligand binding properties of the three apo-TrpR proteins is discussed.

Telephone reminders increase re-screening in a county breast screening program.

INTRODUCTION: Mammography can reduce breast cancer mortality through routine screening. We tested an intervention to increase re-screening in a county program. METHODS: The program requires enrollment before screening. We randomized women who had previously been screened by the program to a telephone call reminder for re-enrollment or usual care (postcard reminder). We followed re-enrollment and re-screening rates for both groups. RESULTS: Compared with the control group (n=610), women in the intervention group (n=599) had higher rates of initial re-enrollment at one month (10% vs. 24%, p<.001) and re-screening at two months (11% vs. 19%, p<.001). These effects persisted over time (five-month re-enrollment: 24% vs. 35%, p<.001; six-month re-screening: 23% vs. 31%, p=.004). The intervention did not alter the odds of a woman's being re-screened once re-enrolled. CONCLUSION: The increase in our re-screening rate after this simple intervention was as great or greater than the rates reported in other studies. A telephone reminder for women previously enrolled in a county breast screening program can increase re-enrollment and subsequent re-screening rates.

The association between the pre-diagnosis mammography screening interval and advanced breast cancer.

BACKGROUND: While screening has been demonstrated to reduce breast cancer mortality, the optimal screening interval is unknown. We designed a study to determine the risk of an advanced breast cancer diagnosis by varying the interval between mammograms. METHODS: We reviewed a single state's mammography records of women diagnosed with breast cancer between 1994 and 2002. The pre-diagnosis screening interval was the number of days between the last two eligible mammograms preceding a cancer diagnosis. The interval was classified as annual (0.75-1.49 years), biennial (1.5-2.49 years) or longer (exceeding 2.49 years). Advanced breast cancer was >or=stage IIB, tumor size >2 cm, or >or=one lymph node with cancer. RESULTS: The probability of an advanced breast cancer diagnosis did not differ between women with an annual pre-diagnosis screening interval and women with a biennial interval (21.1% vs. 23.7%, P=0.262). A longer pre-diagnosis screening interval was weakly associated with advanced breast cancer (21.8% for intervals 0.75-2.49 years vs. 26.8% for longer intervals, P=0.070). In multivariate analysis, we found an interaction between the pre-diagnosis screening interval and age. Among women 50 years or older, the risk of an advanced breast cancer diagnosis risk was higher for women with a pre-diagnosis screening interval exceeding 2.49 years compared to women with shorter screening intervals (OR 1.99 [1.02-3.90]). CONCLUSIONS: We found no difference in advanced breast cancer rates between women using mammography annually or biennially. Among women 50 years or older, the advanced breast cancer rate increased when the pre-diagnosis screening interval exceeded 2.49 years.

Developing a simpler measure of diabetes care quality.

The researchers developed a diabetes care quality summary score (DCQSS) that weights blood pressure, tobacco use, glucose information, and lipid information by cost-effectiveness for improving cardiovascular outcomes. They compared the DCQSS to selected Diabetes Quality Improvement Project (DQIP) measures of care in an urban Medicaid healthcare maintenance organization population using a retrospective chart review. The DCQSS assesses cardiovascular risk compared to individual risk-factor control with DQIP measures. The authors believe that the DCQSS provides an easier interpretation of diabetes quality than multiple DQIP measures.

Costs of follow-up after potentially curative treatment for extremity soft-tissue sarcoma.

Soft-tissue sarcoma is an uncommon cancer with the potential for high rates of recurrence after initial therapy. Multiple surveillance strategies have been developed to follow patients after primary treatment. The purpose of this study was to quantify the costs associated with various published post-treatment surveillance strategies. A literature review covering the years 1982-2003 was performed to find all modern published surveillance methods for extremity soft-tissue sarcoma. Only articles describing an explicit 5-year follow-up strategy were included. Total costs of 5-year follow-up were calculated for each strategy using Medicare-allowed charges as a proxy. Thirty-four articles depicting 54 strategies were identified. Total Medicare-allowed charges in year 2003 dollars ranged from 485 dollars for follow-up of low-grade sarcoma to 21,235 dollars for follow-up of high-grade sarcoma, a 42.8-fold cost differential. The average charge for these 54 strategies was 6,401 dollars. Physical examination and chest x-ray were the most commonly used screening modalities. Several guidelines have been proposed for extremity soft-tissue sarcoma patient follow-up, most prominently those of the National Comprehensive Cancer Network. The literature has yet to reflect the consensus these guidelines suggest. This study shows wide disparity in the costs of 54 specific methods of following soft-tissue sarcoma patients. Clinical trials are needed to identify an optimal surveillance strategy, one balancing gains in survival, quality of life, costs, and societal willingness to expend resources. Such trials have not been conducted due to the rarity of extremity soft-tissue sarcomas and the costs associated with conducting long-term trials. Alternatively, prospective evaluation of imaging modalities used in follow-up should be assessed as part of other trials. Computer simulation analysis also holds great promise as an assessment tool for surveillance strategies because patient participation is not required.

Adapting root cause analysis to chronic medical conditions.

BACKGROUND: Root cause analysis (RCA), used to study the conditions leading to acute accidents, was adapted to analyze adverse events in chronic medical conditions. METHODS: RCA was modified to investigate "trigger events"--markers of potential adverse events--in outpatient diabetes care. For 20 cases with the trigger event of hypoglycemia evidenced by an A1C of > or = 11%, a multidisciplinary team reviewed the findings of medical record abstractions, provider interviews, and patient interviews for each case. The RCA team identified active failures, error-producing conditions, latent conditions, and defenses leading to the trigger event in each case. RESULTS: The methodology identified potential root causes of persistent hyperglycemia. Latent conditions, error-producing conditions, and active failures occurred at the assessment, planning, and implementation phases of a diabetes visit. Recurring failure modes were identified within and across cases. CONCLUSION: RCA can be used to study trigger events in medical care for chronic conditions. Although the data collection occurs months after the event, this methodology can identify variations in chronic care and stimulate discussion about potential solutions.