Metoclopramide-Induced Normalization of Impaired Gastric Emptying in Spinal Cord Injury

In a partial, two-way crossover study of gastric emptying (GE) in spinal cord injury (SCI), fasted, healthy, unmedicated male volunteers were given a 99mTc-labeled liquid meal on two occasions. Metoclopramide (10 mg) was administered intravenously to each subject before the second evaluation of GE. We used single and multiexponential models with linear and nonlinear least-squares regression techniques to study the time-course of the disappearance of 99mTc from the stomach. The GE pattern in all subjects was most accurately characterized by nonlinear analysis (NONLIN) and consisted of two components, an initial adynamic phase and a phase of rapid emptying. The GE t1/2 of a liquid meal decreased from 106.6 +/- 58.3 min (mean +/- SD) in all SCI subjects (quadriplegic plus paraplegic) prior to treatment to 21.6 +/- 8.2 min after the intravenous administration of metoclopramide (p less than 0.006). Significant correlations between GE t1/2 and injury duration (yr) or level of spinal injury were observed. Impaired gastric emptying in SCI can be pharmacologically modified by metoclopramide to resemble a normal gastric emptying profile. Metoclopramide-altered gastric emptying in SCI may be expected to result in changes in the therapeutic efficacy of orally administered drugs when drug absorption is dependent on gastric motility or emptying efficiency.     

Clonal evolution of high‐grade serous ovarian carcinoma from primary to recurrent disease

High‐grade serous carcinoma (HGSC) is the most common and fatal form of ovarian cancer. While most tumours are highly sensitive to cytoreductive surgery and platinum‐ and taxane‐based chemotherapy, the majority of patients experience recurrence of treatment‐resistant tumours. The clonal origin and mutational adaptations associated with recurrent disease are poorly understood. We performed whole exome sequencing on tumour cells harvested from ascites at three time points (primary, first recurrence, and second recurrence) for three HGSC patients receiving standard treatment. Somatic point mutations and small insertions and deletions were identified by comparison to constitutional DNA. The clonal structure and evolution of tumours were inferred from patterns of mutant allele frequencies. TP53 mutations were predominant in all patients at all time points, consistent with the known founder role of this gene. Tumours from all three patients also harboured mutations associated with cell cycle checkpoint function and Golgi vesicle trafficking. There was convergence of germline and somatic variants within the DNA repair, ECM, cell cycle control, and Golgi vesicle pathways. The vast majority of somatic variants found in recurrent tumours were present in primary tumours. Our findings highlight both known and novel pathways that are commonly mutated in HGSC. Moreover, they provide the first evidence at single nucleotide resolution that recurrent HGSC arises from multiple clones present in the primary tumour with negligible accumulation of new mutations during standard treatment.     

MUSHROOM BODY INFLUENCE ON LOCOMOTOR ACTIVITY AND CIRCADIAN RHYTHMS IN DROSOPHILA MELANOGASTER

Whether or not mechanisms underlying circadian locomotor rhythms and learning are related anatomically through the mushroom bodies (MBs) was investigated by monitoring behavioral rhythmicity in flies with MB lesions induced by chemical ablation and by mutations in five different genes. All flies tested were later examined histologically to assess (1) MB neuroanatomy, and (2) the condition of the putative pacemaker cells -- the ventral Lateral Neurons (LN v s) and their terminals that project to the vicinity of the MB calyces. All groups of flies had normal rhythms except for mushroom body miniature ( mbm ; only in a wild-type Berlin genetic background) and mushroom body defect ( mud ). MB ablation had no effect on the gender-specific differences in the rhythmic activity profile that are typical of wild-type flies. However, ablated males had a slightly longer period than untreated males and were more active under constant dark conditions. LN v s and their arborization patterns appeared normal in MB-ablated and in most mutant flies. Activity defects of mbm flies were attributed to genetic background rather than to the mutation alone. Misrouted LN v projections and ～14% arrhythmia of mud flies were uncorrelated and attributed to pleiotropy rather than to specific effects of MB lesions. Our results imply that MBs are not involved in circadian activity rhythms but that they do have an inhibitory effect on activity levels of male flies.     

Musculoskeletal anatomy and nomenclature of the mammalian epipubic bones

Despite the well-established anatomy nomenclature for the marsupial skeleton, there are no names for the epipubic bone structures. Epipubic bones are paired bones articulating with the pubis and projecting cranially in the ventral body wall, present on the pelvic girdle of cynodonts, monotremes and marsupials. These bones were commonly thought to be related to pouch support in marsupials and more recently associated with locomotion. The parts of the epipubic bones have not been named and this has impeded proper morphological analysis. We analyzed the epipubic bones of 302 skeletons comprising American and Australian marsupials, as well as 27 monotreme skeletons, and dissected 10 marsupials for myological attachments analysis. We suggest the following nomenclature for the epipubic bone structures: crest for the cranial end, shaft for the body of the bone, lateral tubercle and the medial articular process. Some markings on the epipubic bone include the oblique line, pertaining to the attachment of external abdominal oblique muscle from the opposite side. The pyramidalis line is the suggested nomenclature for the pyramidalis muscle attachment and the inguinal ligament line for the inguinal ligament attachment. Regarding myology and attachments, based on dissections and review of the literature, the muscles pyramidalis, pectineus, external and internal abdominal oblique, transversus abdominis and rectus abdominis and the structures linea alba, linea semilunaris and the inguinal ligament are connected to the epipubic bone. As has been previously noted, anatomically, epipubic bones are so named due to their position (epi—above, pubic—pubis), and the same applies to structures such as the “epipubic process” or “epipubic cartilage” in amphibians and reptiles. While testing epipubic bone homology in vertebrates is beyond the scope of this work, we believe that using “epipubic bones” or epipubic cartilage/process as standardized terms for the structures found in the most cranial part of the superior ramus of the pubis would facilitate better anatomical communication. This should be valid for other similar terms, such as “epipubes” or “prepubis”, that might occur in the literature in relation to this same physiographic position, and it should also be named as epipubic. We believe that this nomenclature will help in future morphologic studies.     

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.     

The chest roentgenogram in pulmonary edema

It has been shown that the chest roentgenogram is a sensitive and accurate pool for detecting and quantitating cardiogenic pulmonary edema. This can be done at the interstitial stage, when it cannot be detected by physical examination. At the same time the chest film can provide useful information about the circulating blood volume. In patients with the ARDS, a characteristic peripheral and patchy distribution of alveolar edema associated with an absence of peribronchial cuffing, septal lines and effusions has been shown. Enlargement of the right side of the heart and main pulmonary artery may precede actual development of edema in ARDS and provide the opportunity for early diagnosis. Radiographic "scoring" in cases of ARDS correlates well with PO2 (measured with an F1O2 = .21) standardized to a PCO2 of 40 mm Hg. The three main forms of lung edema (that is, cardiogenic, renal or overhydration, and injury edema) appear to have radiographic features that can be used to separate them. The accuracy and objectivity of this approach has been confirmed by taking the radiographic signs as input variables for discriminant analysis. Different hemodynamic conditions and changes of the extravascular protein osmotic forces may be the main factors underlying the radiographic patterns in the various types of pulmonary edema.