Faculty Bibliography

Osteogenesis imperfecta (OI) is typically caused by mutations in type 1 collagen genes, but in recent years new recessive and dominant forms caused by mutations in a plethora of different genes have been characterized. OI type V is a dominant form caused by the recurrent (c.-14C > T) mutation in the 5'UTR of the IFITM5 gene. The mutation adds five residues to the N-terminus of the IFITM5, but the pathophysiology of the disease remains to be elucidated. Typical clinical features present in the majority of OI type V patients include interosseous membrane calcification between the radius and ulna and between the tibia and fibula, radial head dislocation, and significant hyperplastic callus formation at the site of fractures. We report a 5-year-old child with clinical features of OI type III or severe OI type IV (characteristic facies, gray sclerae, typical fractures) and absence of classical features of OI type V with a de novo recurrent IFITM5 mutation (c.-14C > T), now typical of OI type V. This highlights the variability of OI caused by IFITM5 mutations and suggests screening for mutations in this gene in most cases of OI where type 1 collagen mutations are absent.

Doripenem-colistin exerts synergy against some, but not all, Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains in vitro. We determined if doripenem MICs and/or ompK36 porin gene mutations impacted the responses of 23 sequence type 258 (ST258), KPC-2-producing strains to the combination of doripenem (8 mug/ml) and colistin (2 mug/ml) during time-kill assays. The median doripenem and colistin MICs were 32 and 4 mug/ml. Doripenem MICs did not correlate with KPC-2 expression levels. Five and 18 strains had wild-type and mutant ompK36, respectively. The most common mutations were IS5 promoter insertions (n = 7) and insertions encoding glycine and aspartic acid at amino acid (aa) positions 134 and 135 (ins aa134-135 GD; n = 8), which were associated with higher doripenem MICs than other mutations or wild-type ompK36 (all P values 8 mug/ml (P = 0.10 and 0.16). Likewise, doripenem-colistin was more active at 12 and 24 h against the wild type/other mutants than ins aa134-135 GD or IS5 mutants (P = 0.007 and 0.0007). By multivariate analysis, the absence of ins aa134-135 GD or IS5 mutations was the only independent predictor of doripenem-colistin responses at 24 h (P = 0.002). In conclusion, ompK36 genotypes identified ST258 KPC-K. pneumoniae strains that were most likely to respond to doripenem-colistin.

BACKGROUND: Potassium-rich diets are inversely associated with blood pressure. Potassium intake before this study had not been objectively measured by using potassium excretion in a population-based sample in the United States. OBJECTIVES: The objectives of the analysis were to 1) report mean potassium excretion in a diverse urban population by using 24-h urine collections, 2) corroborate potassium excretion by using self-reported fruit and vegetable consumption, and 3) characterize associations between potassium excretion and socioeconomic indicators and access to produce. DESIGN: Participants were from the 2010 Community Health Survey Heart Follow-Up Study-a population-based study including data from 24-h urine collections. The final sample of 1656 adults was weighted to be representative of New York City (NYC) adults as a whole. RESULTS: Mean urinary potassium excretion was 2180 mg/d, and mean self-reported fruit and vegetable intake was 2.5 servings/d. Adjusted urinary potassium excretion was 21% lower in blacks than in whites (P < 0.001), 13% lower in non-college graduates than in college graduates (P < 0.001), and 9% lower in the lowest-income than in the highest-income group (P = 0.03). Potassium excretion was correlated with fruit and vegetable intake. Most NYC residents reported a <10-min walk to fresh fruit and vegetables; this indicator of access was not associated with potassium excretion or fruit and vegetable intake. CONCLUSIONS: Potassium intake is low in NYC adults, especially in lower socioeconomic groups. Innovative programs that increase fruit and vegetable intake may help increase dietary potassium and reduce hypertension-related disease. This trial is registered at clinicaltrials.gov as NCT01889589.

INTRODUCTION/BACKGROUND:Neuroendocrine and pituitary tumors are uncommon tumors that develop from cells of the (neuro-)endocrine system. They can secrete hormones, leading to typical symptoms and syndromes. The cornerstone of antisecretory treatment for neuroendocrine and growth hormone-secreting pituitary tumors consists of somatostatin analogs, which target the somatostatin receptors that are expressed on the tumor cell membrane. Somatostatin analogs activate the second messenger pathways that inhibit hormone secretion and may also delay tumor growth. AREAS COVERED/METHODS:Recent developments in the field of somatostatin analogs and promising new angles in neuroendocrine tumor treatment are discussed. The recently approved somatostatin analog pasireotide and promising new analogs KE108 and somatoprim are reviewed. Further, innovative developments in the field of receptor manipulation, such as epigenetic manipulation and viral somatostatin receptor subtype-2 expression vectors, are discussed, as well as oncolytic viruses specifically targeting neuroendocrine tumor cells. EXPERT OPINION/CONCLUSIONS:In addition to the development of novel somatostatin analogs and refining treatment with existing somatostatin analogs, alternative treatments targeting the somatostatin receptors that aim at increasing the number of somatostatin receptors should be explored as well, thereby broadening treatment perspectives and increasing options for prolonging survival.

OBJECTIVES: Intensivist-performed focused sonography, including renal sonography, is becoming accepted practice. Whether internal medicine residents can be trained to accurately rule out renal obstruction and identify sonographic findings of chronic kidney disease is unknown. The purpose of this study was to test the ability of residents to evaluate for this specific constellation of findings. METHODS: Internal medicine residents were trained in a 5-hour module on focused renal sonography evaluating renal length, echogenicity, hydronephrosis, and cysts on a convenience sample of medical ward, intermediate care, and medical intensive care unit patients. All patients underwent comprehensive sonography within 24 hours. The primary outcome was represented by the Fleiss kappa statistic, which indicated the degree of interobserver agreement between residents and radiologists. Sensitivity, specificity, and positive and negative predictive values were calculated using the comprehensive radiologist-read examination as the reference. RESULTS: Seventeen internal medicine residents imaged 125 kidneys on 66 patients. The average number of studies performed was 7.3 (SD, 6.6). Residents demonstrated excellent agreement with radiologists for hydronephrosis (kappa = 0.73; P < .001; SE, 0.15; sensitivity, 94%; specificity, 93%), moderate agreement for echogenic kidneys (kappa = 0.43; P < .001; SE, 0.13; sensitivity, 40%; specificity, 98%), and substantial agreement for renal cysts (kappa = 0.61; P < .001; SE, 0.12; sensitivity, 60%; specificity, 96%). Residents showed sensitivity of 100% and specificity of 88% for identification of atrophic kidneys, defined as length less than 8 cm. CONCLUSIONS: After a 5-hour training course, medical residents accurately identified hydronephrosis and key sonographic findings of chronic kidney disease in a cohort of medical patients. Screening for hydronephrosis and renal atrophy can be performed by medical residents after adequate training.

OBJECTIVE: To track agreement between single positron emission computed tomography (SPECT) V/Q and CT angiography in patients with high clinical suspicion of pulmonary embolism (PE). If significant agreement occurs, a case could be made for more frequent use of chest radiography followed by SPECT V/Q scanning given its lower risk profile. INTRODUCTION: Diagnosis of PE can be difficult. CT pulmonary angiography (CTA) is the preferred initial test, but may be indeterminate, is a significant source of ionizing radiation, and is contraindicated in renal insufficiency. SPECT ventilation/perfusion imaging (V/Q) is therefore preferred in certain patients. METHODS: Two thousand nine hundred and twenty patients admitted to a tertiary care hospital in New York City were screened and 100 consecutive high-risk patients who required both CTA and V/Q for an initial indeterminate or negative imaging test despite a high pre-test probability were identified. The agreement between these tests was evaluated. RESULTS: There was no significant agreement between CTA and V/Q when positive, negative and indeterminate results were included (K = 0.18, SE = 0.09, p = 0.051). However, in the presence of a positive finding on either test, there was substantial agreement between the two (K = 0.62, SE = 0.27, p = 0.02). In 30 cases in which CTA was indeterminate, V/Q was diagnostic 93 % of the time. In 12 cases in which V/Q was indeterminate, CTA was diagnostic 83 % of the time and negative in 100 % of those cases. CONCLUSION: In the presence of an indeterminate CTA in patients with high clinical suspicion of PE, SPECT V/Q often provides a diagnosis.

Glucocorticoids regulate many physiological processes and have an essential role in the systemic response to stress. For example, gene transcription is modulated by the glucocorticoid-glucocorticoid receptor complex via several mechanisms. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Differences in sensitivity to glucocorticoids in healthy individuals are partly genetically determined by functional polymorphisms of the gene that encodes the glucocorticoid receptor. Hereditary syndromes have also been identified that are associated with increased and decreased sensitivity to glucocorticoids. As a result of their anti-inflammatory properties, glucocorticoids are widely used in the treatment of allergic, inflammatory and haematological disorders. The variety in clinical responses to treatment with glucocorticoids reflects the considerable variation in glucocorticoid sensitivity between individuals. In immune-mediated disorders, proinflammatory cytokines can induce localized resistance to glucocorticoids via several mechanisms. Individual differences in how tissues respond to glucocorticoids might also be involved in the predisposition for and pathogenesis of the metabolic syndrome and mood disorders. In this Review, we summarize the mechanisms that influence glucocorticoid sensitivity in health and disease and discuss possible strategies to modulate glucocorticoid responsiveness.

BACKGROUND: Co-occurrence of lower respiratory symptoms (LRS) and posttraumatic stress disorder (PTSD) has been increasingly recognized among responders and survivors of the World Trade Center (WTC) disaster. Information is limited on the degree which comorbidity intensifies symptoms and compromises quality of life across exposed groups. METHODS: Among responders who completed the first and second Registry surveys, measures of respiratory illness, psychological distress, and diminished quality of life were compared between responders comorbid for LRS and PTSD and responders with only LRS or PTSD. RESULTS: Of 14,388 responders, 40% of those with LRS and 57% of those with PTSD were comorbid. When demographic and WTC exposure-related factors were controlled, comorbid responders compared to those with LRS alone were twice as likely to have frequent dyspnea and to have sought care for dyspnea. Compared to responders with PTSD alone, comorbid responders were 2.1 times more likely to report intense re-experiencing of the disaster, 2.5 times more likely to express feelings of significant non-specific psychological distress, and 1.4 times more likely to have received mental health care. Comorbid responders were approximately three times more likely to report only fair or poor general health and more than twice as likely to report being unable to perform usual activities for >/=14 of 30 days before interview. CONCLUSIONS: Outcomes in comorbid responders were similar to or more severe than in comorbid survivors. Health care and disaster relief providers must suspect comorbid illness when evaluating responders' respiratory or mental illnesses and consider treatment for both.