Autonomic dysfunction in hereditary spastic paraplegia type 4.

BACKGROUND AND PURPOSE: SPAST mutations are the most common cause of hereditary spastic paraplegia (SPG4-HSP), which is characterized by progressive lower limb weakness, spasticity and hyperreflexia. There are few studies about non-motor manifestations in this disease and none about autonomic involvement. Therefore, the aim was to determine the frequency and pattern of autonomic complaints in patients with SPG4-HSP, as well as to determine the clinical relevance and the possible factors associated with these manifestations. METHODS: Thirty-four molecularly confirmed SPG4 patients were recruited in a multicenter cross-sectional study, of whom 26 underwent detailed neurophysiological testing (heart rate variability, sympathetic skin response and the Quantitative Sudomotor Axonal Reflex Test). The Scales for Outcomes in Parkinson's Disease - Autonomic Questionnaire (SCOPA-AUT) was applied to quantify the severity of autonomic symptoms. Results were compared with 44 age- and gender-matched healthy controls using non-parametric tests. P values <0.05 were considered significant. RESULTS: In the SPG4-HSP group, there were 18 men with a mean age of 47.7 ± 12.6 years. SCOPA-AUT scores were similar between patients and controls (P = 0.238). Only the urinary domain subscore was significantly higher amongst patients (4 vs. 2.5, P = 0.05). Absent sympathetic skin response in the hands and feet was more frequent amongst patients (20% vs. 0%, P < 0.001, and 64% vs. 0%, P = 0.006, respectively). Quantitative Sudomotor Axonal Reflex Test responses were also smaller throughout all recording regions in the SPG4-HSP group. CONCLUSION: Our results indicate that SPG4-HSP patients have sudomotor dysfunction caused by damaged small post-ganglionic cholinergic fibers. Damage in SPG4-HSP extends to the peripheral nervous system.

Antiviral medications for the treatment of hepatitis B and C infection and their effects on kidney function.

Over the last decade, treatment options for chronic hepatitis B and hepatitis C infection have markedly evolved. Several Food and Drug Administration-approved drugs are now available for the treatment of chronic hepatitis B, including immunomodulators (standard and pegylated interferon alpha), nucleoside analogues (lamivudine, entecavir and telbivudine) and nucleotide analogues (adefovir dipivoxil and tenofovir). For hepatitis C, the FDA-approved therapies include peginterferon-α, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir with expected approval of more agents in the foreseeable future. Some of these antiviral medications have been reported to have nephrotoxic effects, particularly with long-standing therapy, although the exact mechanism has not been fully elucidated. Secondary forms of glomerulonephritis that can be associated with hepatitis B and hepatitis C viral infection can further complicate the evaluation of renal failure in this population. Knowledge of the different antiviral medications and their potential nephrotoxic effects is crucial, since early identification and substitution to a different agent with withdrawal of the offending medication, may result in recovery or stabilization of renal function. Close monitoring of renal function while taking new antiviral medications is recommended, as some of the nephrotoxic effects may only appear after long-term use.

Granulomatous prostatitis due to Cryptococcus neoformans: diagnostic usefulness of special stains and molecular analysis of 18S rDNA.

A 57-year-old Japanese man complained of pain on micturition. The prostate was of normal size but hard. Transrectal needle biopsy demonstrated granulomatous prostatitis with small focal abscesses. Staining with periodic acid-Schiff, Grocott's methenamine silver and Fontana-Masson revealed yeast-form fungus in the granulomas. The mucoid capsule of the fungus stained with mucicarmine. PCR specific for cryptococcal 18S rDNA using DNA extracted from the pathological specimen was positive, and the sequence was homologous to Cryptococcus neoformans. A diagnosis of cryptococcal granulomatous prostatitis was made. The patient was then found to suffer from meningitis and lung abscess, and was treated with amphotericin B and flucytosine. Careful histological and molecular studies are beneficial to reach the correct diagnosis and to prevent an unfavorable outcome of disseminated cryptococcosis.

HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination.

An ATM-dependent cellular signal, a DNA-damage response, has been shown to be involved during infection of human immunodeficiency virus type-1 (HIV-1), and a high incidence of malignant tumor development has been observed in HIV-1-positive patients. Vpr, an accessory gene product of HIV-1, delays the progression of the cell cycle at the G2/M phase, and ATR-Chk1-Wee-1, another DNA-damage signal, is a proposed cellular pathway responsible for the Vpr-induced cell cycle arrest. In this study, we present evidence that Vpr also activates ATM, and induces expression of gamma-H2AX and phosphorylation of Chk2. Strikingly, Vpr was found to stimulate the focus formation of Rad51 and BRCA1, which are involved in repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), and biochemical analysis revealed that Vpr dissociates the interaction of p53 and Rad51 in the chromatin fraction, as observed under irradiation-induced DSBs. Vpr was consistently found to increase the rate of HR in the locus of I-SceI, a rare cutting-enzyme site that had been introduced into the genome. An increase of the HR rate enhanced by Vpr was attenuated by an ATM inhibitor, KU55933, suggesting that Vpr-induced DSBs activate ATM-dependent cellular signal that enhances the intracellular recombination potential. In context with a recent report that KU55933 attenuated the integration of HIV-1 into host genomes, we discuss the possible role of Vpr-induced DSBs in viral integration and also in HIV-1 associated malignancy.

Chronic granulomatous pleuritis caused by nocardia: PCR based diagnosis by nocardial 16S rDNA in pathological specimens.

Nocardiosis is an uncommon infection caused by the aerobic actinomycete nocardia. Identification of the pathogen is essential for the definitive diagnosis and for an effective treatment. This report describes a case of chronic granulomatous pleuritis caused by nocardia. A 59 year old Japanese man had a history of repeated pyothorax. Right pleural decortication and thoracic drainage were performed. Microbiological examinations of the drained fluid failed to identify a pathogen. Pathological examinations revealed Gram positive filamentous and branching bacilli in the granulomatous lesion of the pleura. Sequencing of the 971 bp 16S ribosomal DNA extracted and amplified from paraffin wax embedded sections identified the microorganism as Nocardia sp. IFM 0860. The patient received sulfamethoxazol/trimethoprim and minocycline. Although the presence of a brain abscess was disclosed by systemic examination, the clinical course has been favourable. In this patient, polymerase chain reaction analysis of 16S ribosomal DNA in pathological specimens was useful in making an accurate diagnosis of nocardiosis and in determining the appropriate treatment.

Portal vein thrombosis after hematopoietic cell transplantation: frequency, treatment and outcome.

Patients who develop veno-occlusive disease (VOD) of the liver may have low plasma levels of the natural anticoagulants protein C and antithrombin III, but large vessel thromboses are not commonly reported in these patients. We reviewed the records of 1847 consecutive patients for evidence of portal vein thrombosis. Eight patients (0.4%) developed portal vein thrombosis (PVT) at a median of day +28 (range 3-58). All patients had clinical evidence of VOD with ascites, a median total serum bilirubin 11.9 mg/dl, and median weight gain from baseline of 7.9%. Median plasma levels of antithrombin III and protein C were low (36% and 21%, respectively). Four patients with PVT died of severe VOD and multi-organ failure, but PVT did not contribute to death. We conclude that PVT is a rare complication of hematopoietic cell transplant and is associated with hepatic VOD. We speculate that PVT resulted from diminished portal venous flow (related to hepatic sinusoidal obstruction to blood flow) and a hypercoagulable state (related to low circulating antithrombin III and protein C levels). Prognosis depended on the severity of the underlying VOD and not PVT per se, suggesting that treatments directed solely toward dissolution of portal vein thrombi should be used with caution in this setting.

Hemifacial myohyperplasia: description of a new syndrome.

Hemifacial hypertrophy is a rare condition characterized by unilateral enlargement of all tissues of the face. We describe three patients who exhibit hemifacial hyperplasia of the muscles of facial expression with no other organ system involvement. These three cases, in addition to six other cases identified in the literature, describe a unique constellation of characteristics that place these patients into a distinct syndrome. We suggest that the term "hemifacial myohyperplasia" be used to describe this specific and unique condition.

Tissue expansion and serial excision in scar revision.

Scars in the head and neck caused by trauma or extirpative surgery can present a significant problem to the patient and may require revision. A variety of techniques, both surgical and nonsurgical, exists for treatment of unsightly scars. Surgical excision of scars relies upon recruitment of local tissue for closure of the ensuing defect. Tissue expansion and serial scar excision may be used to provide more tissue for advancement or local flap coverage of revised scars. Herein we review the history, technique, and complications of tissue expansion and serial excision as well as the basic scientific principles underlying these techniques.

Involvement of benzodiazepine binding sites in an antiaggressive effect by 5-HT(1A) receptor activation in isolated mice.

The effect of the benzodiazepine receptor antagonist flumazenil was examined on an antiaggressive effect of (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3- benzodioxole HCl (MKC-242), a 5-HT(1A) receptor agonist. MKC-242 (0.1-1.0 mg/kg, p.o.) selectively reduced isolation-induced aggressive behavior in a dose-dependent manner. Flumazenil (10 mg/kg, i.p.) antagonized the antiaggressive effects of MKC-242 and diazepam, although it alone did not affect the behaviors of isolated mice. These findings suggest that a gamma-aminobutyric acid(A) (GABA(A)) receptor system is involved in the antiaggressive effect by 5-HT(1A) receptor activation.

Measuring cosmetic facial plastic surgery outcomes: a pilot study.

OBJECTIVE: To test 4 previously published outcomes instruments (the Facelift Outcomes Evaluation, the Rhinoplasty Outcomes Evaluation, the Blepharoplasty Outcomes Evaluation, and the Skin Rejuvenation Outcomes Evaluation) in terms of their reliability and validity in assessing patient-related outcomes of surgical intervention. DESIGN: A prospective pilot study of 78 patients in 3 similar private cosmetic surgery centers undergoing a total of 100 face-lift, rhinoplasty, blepharoplasty, and skin rejuvenation procedures. Patients were evaluated at 2 preoperative and 1 postoperative time points and the instruments were analyzed with regard to their test-retest reliability, internal consistency, and responsiveness to change. RESULTS: All 4 outcomes instruments had excellent reliability, consistency, and validity scores. Test-retest reliability was 0.74 to 0.83 (Pearson correlation coefficients), internal consistency scores were.83 to.88 (Cronbach alpha), and responsiveness to change was statistically significant for each instrument tested (P< or =.001). In addition, patients experienced significant quality of life improvement, with overall satisfaction increasing on average from 37% to more than 84% after these procedures. CONCLUSIONS: These 4 instruments are reliable and valid and can be used to accurately assess patient-related satisfaction in studies of face-lift, rhinoplasty, blepharoplasty, and skin resurfacing outcomes. These brief questionnaires provide the cosmetic surgeon with quantitative tools to evaluate otherwise subjective and purely qualitative outcomes and are recommended for use in future prospective studies.

Skin anatomy and flap physiology.

This article focuses on three main areas, which includes an overview of skin anatomy, different types of skin flaps and their vascular supply, and several aspects of flap biomechanics to allow the surgeon to perform the most adequate reconstruction with regard to location and size of defects.

Cheek repair.

The cheek, one of the most important facial aesthetic units, adjoins key facial structures including the mouth, nose, and eyelids. When undertaking cutaneous cheek defect repair, these functional structures must remain undisturbed. Indeed, the size, depth, and position of each defect must be critically assessed in relation to surrounding donor tissue and landmarks. This article reviews cheek anatomy, surface landmarks, and the various surgical options for achieving successful aesthetic and functional repair.

Severe gastrointestinal bleeding after hematopoietic cell transplantation, 1987-1997: incidence, causes, and outcome.

OBJECTIVE: Severe GI bleeding after hematopoietic cell transplantation is commonly due to lesions that are unusual in nontransplant patients. The frequency of GI bleeding appears to have decreased over the last decade, but the reasons have not been readily apparent. We sought to determine the incidence of severe bleeding during two time periods, to describe the causes and outcomes of bleeding, and to analyze the reasons behind an apparent decline in severe bleeding over the decade covered. METHODS: During 1986-1987 and 1996-1997, we followed all patients with and without severe bleeding at our institution, a marrow transplant center. RESULTS: Over this decade, the incidence of severe bleeding declined from 50/467 (10.7%) to 15/635 (2.4%) (p < 0.0001). Overall mortality from intestinal bleeding declined from 3.6% to 0.9% (p = 0.002), but mortality in those with bleeding remained high (34% vs 40%). The onset (day 42 vs 47) and platelet counts (35,994 vs 37,600/microl) were similar, but the sites and causes of bleeding were different. During 1986-1987, 27/50 patients bled from multiple GI sites, viral and fungal ulcers, or graft-versus-host disease (GVHD). Over the decade, bleeding from GVHD had decreased 80% (p < 0.0001), and bleeding from viral (p < 0.0001) and fungal (p = 0.023) ulcers almost disappeared. CONCLUSIONS: The incidence of severe GI bleeding has declined significantly over the last decade because of prevention of viral and fungal infections and severe acute GVHD. However, severe bleeding after transplant remains a highly morbid event, particularly among patients with GVHD.

5-Hydroxytryptamine-induced outward currents mediated via 5-HT(1A) receptors in neurons of the rat dorsolateral septal nucleus.

Effects of 5-hydroxytryptamine (5-HT) on neurons of the rat dorsolateral septal nucleus (DLSN) were examined by intracellular and whole-cell patch-clamp recording techniques. An outward current was induced by 5-HT (1-100 microM) in a concentration-dependent manner. The EC(50) for 5-HT was 4.8 microM. Also, 8-OH-DPAT (10-100 microM) produced the outward current an EC(50) of 17 microM. Amplitudes of the outward currents produced by 5-HT (100 microM) and 8-OH-DPAT (100 microM) were 117+/-4 (n=6) and 58+/-8 pA (n=6), respectively. Fluvoxamine (200 nM), a specific serotonin re-uptake inhibitor, enhanced the 5-HT (1 microM)-induced outward current: the EC(50) for 5-HT was 0.5 microM in the presence of fluvoxamine (200 nM). L-694247 (100 microM) and CP 93129 (100 microM) also produced outward currents with amplitudes of 33+/-3 (n=4) and 18+/-5 pA (n=4), respectively in DLSN neurons. DOI (100 microM) and RS 67333 (100 microM) did not produce outward currents. NAN-190 shifted, in a parallel manner, the concentration-response relationship of 5-HT to the right. The Lineweaver-Burk plot of the concentration-response curve showed that NAN-190 depressed the 5-HT-induced current in a competitive manner. The current-voltage relationship indicates that the 5-HT-induced current reversed polarity at a potential close to the equilibrium potential of K(+). Ba(2+) (100 microM-1 mM) partially depressed the outward current produced by 5-HT. These results suggest that 5-HT induces multiple K(+) currents via 5-HT(1A) receptors in DLSN neurons.

Microvascular free flap reconstructive options in patients with partial and total maxillectomy defects.

OBJECTIVE: To evaluate and discuss the free flap reconstructive options for patients with partial and total maxillectomy defects. DESIGN: Retrospective review of cases. SETTING: Two tertiary referral centers. PATIENTS: Fifty-one patients had partial or total maxillectomy defects resulting from oncologic surgical resection, and 7 had partial maxillectomy defects resulting from trauma. Inferior or partial maxillectomy defects included 10 anterior arch and hemipalate defects and 12 subtotal or total palate defects. Total maxillectomy defects with and without orbital exenteration included 36 maxilla defects with hemipalate and malar eminence. INTERVENTION: There were 11 fibula, 14 rectus abdominis, 9 scapular, 10 radial forearm, 5 latissimus dorsi, and 13 combination latissimus dorsi and scapular flaps. MAIN OUTCOME MEASURES: Separation of the oral cavity from the sinonasal cavities, diet, type of dental restoration, type of orbital restoration, speech intelligibility, and complications. RESULTS: Only 1 flap failure was reported. There was loss of bone in 2 flaps and loss of the skin paddle in 1 flap. All palatal defects were sealed by the separation of the oral and sinonasal cavities. Thirty-eight patients were able to eat a regular diet while the remaining patients maintained a soft diet. All patients conversed on the telephone without difficulty in intelligibility. Eight patients had an implant-borne dental prosthetic, and 30 patients had a conventional partial prosthetic. Orbit restoration was achieved in 2 patients with an implant-borne prosthetic, and 6 patients retained a standard orbit prosthetic. CONCLUSIONS: Free flap reconstruction of the maxilla creates reproducible permanent separation of the oral and sinonasal cavities in a single-stage procedure. In addition, there exists the potential for dental rehabilitation with restoration of masticatory and phonatory function. Free flap reconstruction also provides a good cosmetic result, which improves patients' outlook and contributes to their overall well-being. Reconstructive flaps are designed to fit specific maxillary defects and patient needs to provide optimally functional and cosmetic results.

Bile duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous hematopoietic cell transplantation.

BACKGROUND: Acute graft-versus-host disease (GVHD) of the liver is a frequent complication of allogeneic hematopoietic cell transplantation. This report describes hepatic GVHD following autologous transplantation. METHODS: We reviewed 116 consecutive autologous transplant recipients. A diagnosis of GVHD was based on histology (segmental to subtotal destruction of bile ductal epithelial cells with apoptosis and lymphocytic infiltrates), clinical criteria (elevated serum alkaline phosphatase), a response to immunosuppressive therapy, and finding no other cause for cholestatic liver disease. RESULTS: Two patients developed cholestatic liver disease (alkaline phosphatase levels over five times the normal upper limit) and had liver biopsies showing apoptotic and dysmorphic ductular epithelial cells typical of GVHD. Three additional patients developed cholestasis and intestinal symptoms but had gastric biopsies only, showing apoptotic crypt epithelial cells and crypt cell drop-out typical of GVHD. CONCLUSION: Two recipients of autologous hematopoietic cells developed histologic abnormalities of small bile ducts and cholestatic liver disease resembling GVHD of the liver after allogeneic transplant. The mechanisms of bile duct damage in this setting may involve immune dysregulation related to reconstitution of immunity with peripheral blood stem cells.

Localization of EMSP1 expression during tooth formation and cloning of mouse cDNA.

Enamel matrix serine proteinase 1 (EMSP1) is a proteolytic enzyme that has been isolated from the developing enamel of pig teeth. Its apparent function is to degrade the organic matrix in preparation for enamel maturation. The expression of EMSP1 has never been investigated in another organism besides the pig, and EMSP1 expression in the enamel organ has never been specifically demonstrated in ameloblasts. Here we report the expression of recombinant pig EMSP 1 (rpEMSP 1), the generation of rabbit polyclonal antibodies against rpEMSP1, the characterization of the antibodies and EMSP1 expression by Western blot and immunohistochemical analyses, the cloning and characterization of a full-length cDNA encoding mouse EMSP1, and the localization of EMSP1 expression in ameloblasts in mouse day 14 first and second molars by in situ hybridization. The full-length mouse EMSP1 cDNA clone has 1,237 nucleotides, excluding the poly(A+) tail, and encodes a preproprotein of 255 amino acids. Mouse EMSP1 shares 75% amino acid identity with pig EMSP1 and has three potential N-linked glycosylation sites, two of which are conserved in the pig homologue. Western blot analysis shows that the polyclonal antibodies are specific for EMSP1 and do not cross-react with trypsin. Immunohistochemistry of pig incisors shows discrete staining in the surface enamel at the earliest part of the maturation stage. In mouse molars, in situ hybridization gives a distinct and specific signal in maturation-stage ameloblasts, and in the junctional epithelium following tooth eruption. We conclude that EMSP1 is expressed by pig and mouse ameloblasts during the early maturation stage of amelogenesis.

Osteotomy techniques to correct posttraumatic deviation of the nasal pyramid: a technical note.

BACKGROUND AND OBJECTIVES: Correction of the deviated nasal pyramid is frequently incomplete and may result in a sub-optimal surgical outcome. Precise anatomic analysis of the deformity and a thorough understanding of available techniques improve the surgical osteotomy. METHODS AND MATERIALS: The advantages and disadvantages of the various osteotomy techniques are analyzed, based on the cadaver studies and clinical experience of the authors. The cadaver studies demonstrate the anatomic results when various osteotomes are used in specified ways. Clinical outcomes in the treatment of posttraumatic nose deviations correlate well with these results. RESULTS AND/OR CONCLUSIONS: A thorough understanding of the advantages and disadvantages of various osteotomy techniques enables the surgeon to apply them to specific anatomical deformities in posttraumatic nose deviations more precisely. In general, perforating osteotomies preserve more soft tissue support than the linear osteotomies. Sequential osteotomies, occasionally combined with intermediate osteotomies, are useful in straightening the extremely deviated nasal pyramid.