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Two patients with homozygous mutations in PDX1 presented with pancreatic agenesis, chronic diarrhea, and poor weight gain, the causes of which were not identified through routine clinical testing. We aimed to perform a deep analysis of the stomach and intestine using organoids derived from induced pluripotent stem cells from PDX1Gastric fundic, antral, and duodenal organoids were generated using induced pluripotent stem cell lines from a PDX1Patient-derived PDX1These patients will now be monitored for the progression of metaplasia and gastrointestinal complications that might be related to the reduced gastric and intestinal endocrine cells. This study demonstrates the utility of organoids in diagnosing uncovered pathologies.

To investigate the role of myosin regulatory light chain isoforms as a determinant of the kinetics of cardiac contraction, unloaded shortening velocity was determined by the slack-test method in skinned wild-type murine atrial cells and transgenic cells expressing ventricular regulatory light chain (MLC2v). Transgenic mice were generated using a 4.5-kb fragment of the murine α-myosin heavy chain promoter to drive high levels of MLC2v expression in the atrium. Velocity of unloaded shortening was determined at 15°C in maximally activating Ca2+solution (pCa 4.5) containing (in mmol/l) 7 EGTA, 1 free Mg2+, 4 MgATP, 14.5 creatine phosphate, and 20 imidazole (ionic strength 180 mmol/l, pH 7.0). Compared with the wild type ( n = 10), the unloaded shortening velocity of MLC2v-expressing transgenic murine atrial cells ( n = 10) was significantly greater (3.88 ± 1.19 vs. 2.51 ± 1.08 muscle lengths/s, P < 0.05). These results provide evidence that myosin light chain 2 regulates cross-bridge cycling rate. The faster rate of cycling in the presence of MLC2v suggests that the MLC2v isoform may contribute to the greater power-generating capabilities of the ventricle compared with the atrium.

Due in part to the growing criticism of the war in Vietnam, Sen. Edward M. Ken-nedy's decision to launch a fact-finding mission to Vietnam in January 1968 generated suspicion and anxiety within the Johnson administration. This paper focuses on the administration's attempt to discredit the Kennedy mission which it viewed as offering a serious, official, and troubling source of dissent. Although the publication of the mission's findings would be overshadowed by the Tet Offensive, the Johnson administration's response seriously undermines its contention that it desired a negotiated settlement.

To investigate the relationship between abdominal ultrasound findings and demographic, historical, and clinical features in children with cystic fibrosis (CF).Children age 3-12 years with CF without known cirrhosis, were enrolled in a prospective, multicenter study of ultrasound to predict hepatic fibrosis. Consensus ultrasound patterns were assigned by 3 radiologists as normal, heterogeneous, homogeneous, or cirrhosis. Data were derived from direct collection and US or Toronto CF registries. χ(2) or ANOVA were used to compare variables among ultrasound groups and between normal and abnormal. Logistic regression was used to study risk factors for having abnormal ultrasound.Findings in 719 subjects were normal (n = 590, 82.1%), heterogeneous (64, 8.9%), homogeneous (41, 5.7%), and cirrhosis (24, 3.3%). Cirrhosis (P = .0004), homogeneous (P.0001), and heterogeneous (P = .03) were older than normal. More males were heterogeneous (P = .001). More heterogeneous (15.0%, P = .009) and cirrhosis (25.0%, P = .005) had CF-related diabetes or impaired glucose tolerance vs normal (5.4%). Early infection with Pseudomonas aeruginosa (2 years old) was associated with a lower risk (OR 0.42, P = .0007) of abnormal. Ursodeoxycholic acid use (OR 3.69, P.0001) and CF-related diabetes (OR 2.21, P = .019) were associated with increased risk of abnormal.Unsuspected cirrhosis is seen in 3.3% of young patients with CF, heterogeneous in 8.9%. Abnormal ultrasound is associated with CF-related diabetes, and early P aeruginosa is associated with normal ultrasound. Prospective assessment of these risk factors may identify potential interventional targets.ClinicalTrials.gov: NCT01144507.

Abstract The structure-function relationships of the sarcomeric proteins in the mammalian cardiac compartment remain ill-defined because of the lack of a suitable model in which they can be readily manipulated or exchanged in vivo. To establish the validity of the transgenic paradigm for remodeling the mammalian heart, the murine α-cardiac myosin heavy chain gene promoter was used to express a ventricular myosin light chain-2 transgene ( MLC2v ) in both the atria and ventricles of the adult animal. Expression resulted in high levels of the transgene’s transcript in both compartments. In the ventricle, the transgene was expressed against the background expression of the normal isoform. In the atrium, the transgene’s expression would be ectopic, in that normally, MLC2v expression is restricted to the ventricle. Ectopic expression of the transgene in the atria resulted in a complete replacement of the atrial myosin light chain-2 protein isoform, although the endogenous isoform’s steady state transcript levels were unchanged. In contrast, ventricular expression of the transgene had no effect at the protein level, despite an eightfold increase in MLC2v transcript levels. The data show that sarcomeric protein stoichiometry is maintained rigorously via posttranscriptional regulation and that protein replacement can be achieved through a single transgenic manipulation.

An effective topical therapy is still needed in the management of warts, especially the plantar and the periungual types. Often cantharidin does not produce deep enough necrosis even with repeated applications and even after debridements of various degrees. In hyperkeratotic types of warts podophyllin has not been effective because of failure to secure deep penetration. Recently, a topical wart therapy was suggested by Lavender.1This was a mixture of trichloroacetic acid—26%, glycerin—21%, and salicylic acid—53%. This was an effective medication. However, often it did not penetrate deeply. Also, the mixture dried out on standing and was difficult to maintain in a fluid or semisolid state. When podophyllin was added to this mixture not only was the mixture more rapid in its action but also more effective. Moreover, it did not dry out on exposure to air. The mixture is composed of the following formula: podophyllin—20%, trichloroacetic acid—25%, glycerin—25%, and