Rare deleterious mutations are associated with disease in bipolar disorder families.

Bipolar disorder (BD) is a common, complex and heritable psychiatric disorder characterized by episodes of severe mood swings. The identification of rare, damaging genomic mutations in families with BD could inform about disease mechanisms and lead to new therapeutic interventions. To determine whether rare, damaging mutations shared identity-by-descent in families with BD could be associated with disease, exome sequencing was performed in multigenerational families of the NIMH BD Family Study followed by in silico functional prediction. Disease association and disease specificity was determined using 5090 exomes from the Sweden-Schizophrenia (SZ) Population-Based Case-Control Exome Sequencing study. We identified 14 rare and likely deleterious mutations in 14 genes that were shared identity-by-descent among affected family members. The variants were associated with BD (P<0.05 after Bonferroni's correction) and disease specificity was supported by the absence of the mutations in patients with SZ. In addition, we found rare, functional mutations in known causal genes for neuropsychiatric disorders including holoprosencephaly and epilepsy. Our results demonstrate that exome sequencing in multigenerational families with BD is effective in identifying rare genomic variants of potential clinical relevance and also disease modifiers related to coexisting medical conditions. Replication of our results and experimental validation are required before disease causation could be assumed.

T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival.

PURPOSE: Preoperative chemoradiation therapy is used widely in the treatment of rectal cancer. The predictive value of response to neoadjuvant remains uncertain. We retrospectively evaluated the impact of response to preoperative and, specifically, of T-level downstaging, nodal downstaging, and complete pathologic response after chemoradiation therapy on oncologic outcome of patients with locally advanced rectal cancer. METHODS: There were 88 patients with ultrasound Stage T3/T4 midrectal (n = 37) and low rectal (n = 51) cancers (63 males; mean age 62.6 years). All patients were treated by preoperative 5-fluorouracil-based chemotherapy and pelvic radiation followed by surgical resection in six weeks or longer (56 sphincter-preserving resections). RESULTS: T-level downstaging after neoadjuvant treatment was demonstrated in 36 (41 percent) of 88 patients, and complete pathologic response was observed in 16 (18 percent) of the 88. Of the 42 patients with ultrasound-positive nodes, 27 had no evidence of nodal involvement on pathologic evaluation (64 percent). The overall response rate (T-level downstaging or nodal downstaging) was 51 percent. At a median follow-up of 33 months, 86.4 percent of patients were alive. The overall recurrence rate was 10.2 percent (three patients had local and six had metastatic recurrences). Patients with T-level downstaging and complete pathologic response were characterized by significantly better disease-free survival (P = 0.03, P = 0.04) and better overall survival (P = 0.07, P = 0.08), according to Wilcoxon's test comparing Kaplan-Meier survival curves. None of the patients with complete pathologic response developed recurrence or died during the follow-up period. CONCLUSION: T-level downstaging and complete pathologic response after preoperative chemoradiation therapy followed by definitive surgical resection for advanced rectal cancer resulted in decreased recurrence and improved disease-free survival. Advanced rectal cancers that undergo T-level downstaging and complete pathologic response after chemoradiation therapy may represent subgroups that are characterized by better biologic behavior.

Practice parameters for the treatment of sigmoid diverticulitis--supporting documentation. The Standards Task Force. The American Society of Colon and Rectal Surgeons.

It should be recognized that these guidelines should not be deemed inclusive of all proper methods of care or exclusive of methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all of the circumstances presented by the individual patient.

Familial lissencephaly with cleft palate and severe cerebellar hypoplasia.

Lissencephaly is a brain malformation characterized by absence of gyral formation, resulting in a smooth brain surface. Histologic study shows severe anomalies of cerebral cortical development. Several lissencephaly syndromes have been described. Here we report a familial syndrome of lissencephaly, cleft palate, diffuse agyria, and severe cerebellar hypoplasia. Microscopic examination of the abnormally thick cerebral cortex showed absence of cortical layering, with preservation of the pia-glial barrier. This is the first report of recurrent lissencephaly with cleft palate and severe cerebellar hypoplasia in which these unique neuropathology findings are described. Autosomal recessive inheritance is suggested by recurrence in sibs within the same family, but germ cell mosaicism for a dominant mutation is not excluded.

Reconstruction of rectovaginal fistula with sphincter disruption by combining rectal mucosal advancement flap and anal sphincteroplasty.

PURPOSE: This study evaluated the effectiveness of combining advancement flap with sphincteroplasty in patients symptomatic with rectovaginal fistula and anal sphincter disruption. METHODS: Twenty patients with rectovaginal fistulas and anal sphincter disruptions after vaginal deliveries underwent combined rectal mucosal advancement flap and anal sphincteroplasty between July 1986 and July 1993. The mean age of the patients was 30 (range, 18-40) years and the mean duration of symptoms was 54.8 weeks (range, 7 weeks to 6 years). In addition to mucosal advancement flap repair, 13 patients underwent two-layer repair of anal sphincters (with reapproximation of the puborectalis in 8 of the patients); 6 patients underwent one-layer overlap repair of anal sphincters (with reapproximation of the puborectalis in 2 of the patients); and 1 patient underwent reapproximation of internal anal sphincter alone because squeeze pressures were adequate, as determined by anal manometry. RESULTS: Postoperatively, vaginal discharge of stool and flatus was eliminated entirely in all 20 patients. Perfect anal continence of stool and flatus was restored in 14 patients (70 percent). Incontinence was improved but not eliminated in six patients (4 incontinent to liquid stool and 2 to flatus), and two patients required perineal pads. Subjectively, 19 patients (95 percent) reported the result as excellent or good. There were no complications. CONCLUSION: The combination of mucosal advancement flap and anal sphincteroplasty is a safe and highly effective procedure for correcting rectovaginal fistula with sphincter disruption after obstetrical injuries.

Mesomelic shortening of the upper extremities with spur formation and cutaneous dimpling.

We report a boy with mesomelic dysplasia of the forearms, skin dimples, mildly bowed tibiae, metatarsus adductus, congenital cataracts, sensorineural hearing loss, hypotonia, and mildly dysmorphic features. Prominent radiologic findings include bony spurs of the diaphyses of the radii bilaterally with angulated, significantly shortened radii and ulnae and elbow dislocations. Changes in the lower extremities are confined to bowing of the tibiae and elongation of the thinned fibulae. To our knowledge this case represents a unique combination of findings not previously reported, although some resemblance was found to a patient reported by Kozlowski et al. in 1993.

Cervical teratoma: prenatal diagnosis and long-term follow-up.

Cervical teratomas are rare tumours which are the result of abnormal prenatal development. They are usually detected at birth, but can occasionally remain silent until adulthood. Obstruction of the airway is the major challenge in the neonatal period. Prenatal diagnosis allows for early consultation with paediatric surgical specialists, so that the time and place of delivery can be addressed, and planning for resuscitative efforts can be organized in advance. If the airway is quickly stabilized and resection of the tumour is not delayed, the prognosis is good. Cervical teratomas in neonates are usually benign; however, malignant transformation and metastasis can occur as a rare event, influencing long-term survival and prognosis. We present two cases of neonatal cervical teratoma detected prenatally by ultrasound. In one case, termination of the pregnancy was elected. In the other case, the child was delivered at 36 weeks' gestation, an airway was secured, and subtotal resection of the tumour was performed. No developmental or neurological deficit has been detected on long-term follow-up at 5 years of age. We present a review of the literature, with attention to outcome and potential for malignancy in neonatal cervical teratomas, in order to provide help in decision-making, once prenatal diagnosis is made.

Endorectal mucosal advancement flap: the preferred method for complex cryptoglandular fistula-in-ano.

Cryptoglandular fistula-in-ano is a common affliction that usually responds well to conventional surgical procedures such as fistulectomy, fistulotomy, and seton placement. These procedures, however, can be associated with varying degrees of fecal incontinence. Endorectal mucosal advancement flap has been advocated as an alternative procedure that avoids this problem. This study was undertaken to determine the risks and benefits associated with endorectal mucosal advancement flap in the treatment of complex fistula-in-ano. One hundred sixty-four patients underwent 167 endorectal mucosal advancement flap procedures for complex cryptoglandular fistula-in-ano between January 1982 and December 1990. There were 126 men and 38 women whose mean age was 42.1 years (range 20 to 79 years). The majority of the patients (70%) had complex fistulas (transsphincteric, suprasphincteric, or extrasphincteric). Fifteen patients (9%) had an intersphincteric fistula. All patients were available for short-term follow-up (6 weeks). Postoperative morbidity was minimal and included urinary retention in 13 patients (7.8%) and bleeding in one patient. Healing time averaged 6 weeks. Long-term follow-up, ranging from 19 to 135 months, was carried out in 61 patients. There were two recurrences (3.28%). Nine patients (15%) complained of varying degrees of fecal incontinence. Six patients complained of incontinence to flatus and three patients complained of incontinence to liquid stool. No patient was incontinent of solid stool. Sixty patients (98%) rated their functional result as excellent or good. Endorectal mucosal advancement flap is a safe and effective technique for the treatment of complex cryptoglandular fistula-in-ano. It can be performed with minimal morbidity, no mortality, an acceptable recurrence rate, and little alteration in anorectal continence.

Gene structure and amino acid sequence of the human cone photoreceptor cGMP-phosphodiesterase alpha' subunit (PDEA2) and its chromosomal localization to 10q24.

The genomic organization and nucleotide structure of the human cone photoreceptor cGMP phosphodiesterase alpha'-subunit (alpha'-PDE) gene (PDEA2) as well as its chromosomal localization have been determined. This gene, which spans about 48 kb, consists of 22 exons and codes for an 858-amino-acid protein. The alpha'-PDE gene maps to human chromosome 10q24. Its coding region shows about 90% nucleotide identity and 93% amino acid identity with the corresponding region of the bovine gene. The intron-exon organization of the genes encoding human cone alpha'-PDE and rod beta-PDE are very similar, suggesting that these proteins have a close phylogenetic relationship and probably a common origin.

Good manufacturing practice and viral safety.

The concept of virus inactivation during the manufacture of blood products raises questions about possible recontamination of the product by the environment. A strict regime of good manufacturing practice (GMP) is mandatory. The guidelines originally issued by the World Health Organization (WHO), and now law in most countries, are an excellent basis for the operation of a production plant. The following elements of GMP require special concern: (i) All functions shall be defined in a clear organization chart. (ii) Personnel shall be appropriately trained for the job and to perfect hygiene. (iii) Buildings and facilities, as well as supply systems, shall exclude the possibility of recontamination of already virus-inactivated materials. (iv) Equipment shall be easy to clean and fully sterilizable. (v) Production shall follow appropriate written procedures. (vi) The Quality Control Organization shall monitor the process by in-process controls and review the records for possible deviations. All GMP issues are coordinated by a Quality Assurance Organization that also reviews the overall performance of the operation. The maintenance of viral safety of the products basically depends upon the full commitment of all bodies involved to proper and non-negotiable GMP.

Colonoscopic bowel preparations--which one? A blinded, prospective, randomized trial.

UNLABELLED: For the past decade peroral, orthograde, polyethylene glycol-electrolyte lavage solutions (PEG-ELS) have been the preferred bowel-cleansing regimens before diagnostic and therapeutic procedures on the colon and rectum. The large volume and unpalatibility of these solutions may lead to troubling side effects and poor patient compliance. PURPOSE: This study was undertaken to determine which of various colon-cleansing methods before colonoscopy would provide greater patient acceptance while maintaining similar or improved effectiveness and safety. METHODS: Three hundred twenty-nine patients undergoing elective ambulatory colonoscopy were prospectively randomized to one of three bowel preparation regimens. Group 1 received 41 of PEG-ELS (n = 124). Group 2, in addition to PEG-ELS, received oral metoclopramide (n = 99). Group 3 received oral sodium phosphate (n = 106). All groups were evenly matched according to age and sex. RESULTS: Ninety-one percent of all patients completed the preparation received. Sixteen percent of patients suffered significant sleep loss with a bowel preparation. When comparing the three groups, there was no difference in the assessment of nausea, vomiting, abdominal cramps, anal irritation, or quality of the preparation. Compared with other preparations, oral sodium phosphate was better tolerated. More patients completed the preparation (P < or = 0.001). Fewer patients complained of abdominal fullness (P < or = 0.001). More patients were willing to repeat their preparation (P < or = 0.02). Also, sodium phosphate was found to be four times less expensive than either of the PEG-ELS preparations. CONCLUSION: All regimens were found to be equally effective. Abdominal symptoms and bowel preparation were not influenced by the addition of metoclopramide. The oral sodium phosphate preparation was less expensive, better tolerated, and more likely to be completed than either of the other preparations.

Myeloid differentiation mediated through retinoic acid receptor/retinoic X receptor (RXR) not RXR/RXR pathway.

Retinoids, such as all-trans-retinoic acid and 9-cis-retinoic acid, are naturally occurring ligands of the nuclear retinoic acid receptors (RARs). In concert with binding of ligand, these receptors from heterodimers with the retinoic X receptor (RXR) and transactivate RAR/RXR-responsive genes. Retinoids can differentiate leukemic cell lines in vitro and induce clinically complete remissions in patients with acute promyelocytic leukemia. Synthetic ligands to the RAR and RXR receptors have been developed that selectively bind and activate RAR/RXR (TTAB) and RXR/RXR dimers (SR11217). We investigated the affect of these ligands, either alone or in combination, on in vitro growth and differentiation of cells from the HL-60, KG-1, THP-1, and WEHI-3 myeloid cell lines as well as on clonal growth of fresh myeloid leukemic blasts from patients. Clonal inhibition of proliferation of these cells was studied in soft agar cultures. Cells were plated in the presence of either one or a combination of retinoids at concentrations of 10(-5) to 10(-10) mol/L. TTAB inhibited 50% clonal growth at an effective dose (ED50) that was about 1,000-fold lower than the concentration of SR11217 required to achieve an ED50 for the same leukemic cells. Combination of both ligands at a variety of concentrations showed no synergistic effects. Superoxide production (nitroblue tetrazolium reduction) and CD11b expression as parameters of differentiation of HL-60 cells were also examined. Results paralleled those of clonal growth, with SR11217 being markedly less potent than TTAB. These results show that the ligand selective for RXR-homodimers has little effect on either inducing differentiation or inhibiting clonal growth of leukemic cells. The differentiating and antiproliferative effects of retinoids are mainly induced through RAR/RXR heterodimers, and development of therapeutic analogs should focus on this category of retinoids.

Is preoperative computerized tomography useful in assessing patients with colorectal carcinoma?

PURPOSE: Controversy exists over the appropriate preoperative evaluation of colorectal cancer patients. Most surgeons agree that basic laboratory studies are indicated. Computerized tomography of the abdomen and pelvis has been used in our practice to augment the preoperative evaluation of these patients. METHODS: One hundred fifty-eight consecutive patients with primary colorectal carcinoma underwent computerized tomography (CT) of the abdomen as part of their preoperative evaluation. Their medical records were retrospectively reviewed. RESULTS: In 88 patients, 120 findings present on CT were otherwise unknown. Of these, 35 percent were clinically significant in that they allowed the surgeon to alter the proposed operative procedure or added additional technical information for consideration preoperatively. Findings include liver metastasis (26), atrophic kidney (3), and abdominal wall or contiguous organ invasion (11). In addition, two other solid organ carcinomas were detected. In the remaining 70 patients, CT contributed no additional pertinent information about the patient prior to this initial operative procedure. CONCLUSIONS: CT aids in the preoperative evaluation of individuals with colorectal carcinoma. It provides important clinical information that is useful to the surgeon planning the procedure. Additionally, CT permits the patient and his family to be aware of their overall status and to subsequent treatment options. Computerized tomography eliminates the need for preoperative intravenous pyelogram, improves the preoperative staging for metastatic disease, and provides a baseline for comparison during the postoperative follow-up period should recurrence be suspected or adjuvant therapy be planned.

Dexamethasone inhibits tumor necrosis factor-induced granulocyte colony-stimulating factor production in human endothelial cells.

Dexamethasone (10(-5)-10(-7) M) is able to suppress the tumor necrosis factor (TNF)-induced production of granulocyte colony-stimulating factor (G-CSF) in human umbilical vein endothelial cells (HUVEC). Using Western-blot analysis and bioassay for the evaluation of G-CSF protein and activity, a significant decrease in TNF-induced production could be found in cells cultured in the presence of dexamethasone as compared to TNF stimulation in the absence of dexamethasone. No inhibition by dexamethasone was seen in endothelial cells stimulated with interleukin 1 beta (IL-1 beta; 10 U/ml). Addition of IL-1 to cultures stimulated with TNF in the presence of dexamethasone could overcome the inhibitory effects of corticosteroids. Suppression of G-CSF production can, at least in part, explain the functional abnormalities of granulocytes found in patients treated with glucocorticosteroids.

Abdominal aortic aneurysmectomy without preoperative angiography. A prospective study.

In an attempt to analyze whether routine angiography is necessary prior to elective abdominal aortic aneurysmectomy (AAA), a prospective study was designed in which this examination was obtained only for specific indications. These included significant hypertension, renal dysfunction, symptoms of visceral ischemia, suprarenal extension of the aneurysm or a coexisting thoracic aneurysm, and diminished or absent femoral pulses. A consecutive series of 124 abdominal aortic aneurysms is reported, in which 110 procedures were performed electively. Preoperative angiograms were obtained in only ten patients (9.1%) and in nine of these an alteration in the usual operative strategy resulted. In the remaining 100 patients undergoing elective AAA without preoperative aortography, acceptable morbidity and mortality rates were obtained despite the intraoperative discovery of iliac aneurysms in 25 patients (23%) and accessory renal arteries in three patients (2.7%). In the absence of specific indications for angiography, the mainstay of the preoperative evaluation for abdominal aortic aneurysms should be computed tomography (CT). The preoperative workup can be done entirely on an outpatient basis.

Limb salvage in elderly patients. Is aggressive surgical therapy warranted?

With the continued increase in life expectancy in the United States, the number of elderly patients presenting with limb-threatening atherosclerotic occlusive disease will also rise. The risk of arterial reconstructive surgery has been considered prohibitive in many of these individuals. During a six-year period, 50 patients aged 80 years or greater underwent a total of 64 surgical procedures for limb-threatening ischemia: 17 men (34%) and 33 women (66%). Ages ranged from 80 to 97 with a mean of 84 years. The procedural mortality rate was 3.1%. Cumulative life table survival rates for these patients were at 1 year, 92%; at 2 years, 76%; and at 3 years, 76%. The cumulative life table limb salvage rates were 92%, 88%, and 83% at the same intervals. Of the patients who died during the follow-up periods, 79% still had their previously-threatened limb intact. The results in these patients, as well as those from other series, support an aggressive policy of arterial reconstruction for elderly patients with limb-threatening ischemia. Age, per se, is not a contraindication to revascularization.